Significance of Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential by Medicinal Plant and Food Ingredients. Hoda M. Eid, Natural Health Products and Metabolic Diseases Laboratory Michelle L. Wright, Emory University N.V Anil Kumar, Manipal University Abdel Qawasmeh, Hebron University Sherif T. S. Hassan, University of Veterinary and Pharmaceutical Sciences Brno Andrei Mocan, Iuliu Hatieganu University of Medicine and Pharmacy Seyed M. Nabavi, Baqiyatallah University of Medical Sciences Luca Rastrelli, University of Salerno Atanas G. Atanasov, Institute of Genetics and Animal Breeding Pierre S. Haddad, Natural Health Products and Metabolic Diseases Laboratory

Journal Title: Frontiers in Pharmacology Volume: Volume 8 Publisher: Frontiers Media | 2017, Pages 387-387 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.3389/fphar.2017.00387 Permanent URL: https://pid.emory.edu/ark:/25593/s4366

Final published version: http://dx.doi.org/10.3389/fphar.2017.00387 Copyright information: © 2017 Eid, Wright, Anil Kumar, Qawasmeh, Hassan, Mocan, Nabavi, Rastrelli, Atanasov and Haddad. This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Accessed September 24, 2021 4:14 PM EDT REVIEW published: 30 June 2017 doi: 10.3389/fphar.2017.00387

Significance of Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential by Medicinal Plant and Food Ingredients

Hoda M. Eid 1, 2, 3, Michelle L. Wright 4, N. V. Anil Kumar 5, Abdel Qawasmeh 6, Sherif T. S. Hassan 7, Andrei Mocan 8, 9, Seyed M. Nabavi 10, Luca Rastrelli 11, Atanas G. Atanasov 12, 13, 14* and Pierre S. Haddad 1, 2*

1 Natural Health Products and Metabolic Diseases Laboratory, Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, Canada, 2 Canadian Institutes of Health Research Team in Aboriginal Antidiabetic Medicines, Montréal, QC, Canada, 3 Department of Pharmacognosy, University of Beni-Suef, Beni-Suef, Egypt, 4 Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, United States, 5 Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal, India, 6 Faculty of Pharmacy, Hebron University, Hebron, Palestine, 7 Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czechia, 8 Department of Pharmaceutical Botany, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania, 9 ICHAT and Institute Edited by: for Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania, 10 Applied Kalin Yanbo Zhang, Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran, 11 Dipartimento di Farmacia, University of Hong Kong, Hong Kong University of Salerno, Fisciano, Italy, 12 Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, 13 14 Reviewed by: Poland, Department of Pharmacognosy, University of Vienna, Vienna, Austria, Department of Vascular Biology and Adeyemi Oladapo Aremu, Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria University of KwaZulu-Natal, South Africa Metabolic syndrome is a cluster of three or more metabolic disorders including insulin Jelena Cvejic, University of Novi Sad, Serbia resistance, obesity, and hyperlipidemia. Obesity has become the epidemic of the *Correspondence: twenty-first century with more than 1.6 billion overweight adults. Due to the strong Atanas G. Atanasov connection between obesity and type 2 diabetes, obesity has received wide attention [email protected] Pierre S. Haddad with subsequent coining of the term “diabesity.” Recent studies have identified unique [email protected] contributions of the immensely diverse gut microbiota in the pathogenesis of obesity and diabetes. Several mechanisms have been proposed including altered glucose and Specialty section: This article was submitted to fatty acid metabolism, hepatic fatty acid storage, and modulation of glucagon-like Ethnopharmacology, peptide (GLP)-1. Importantly, the relationship between unhealthy diet and a modified gut a section of the journal microbiota composition observed in diabetic or obese subjects has been recognized. Frontiers in Pharmacology Similarly, the role of diet rich in polyphenols and plant polysaccharides in modulating gut Received: 28 February 2017 Accepted: 02 June 2017 bacteria and its impact on diabetes and obesity have been the subject of investigation Published: 30 June 2017 by several research groups. Gut microbiota are also responsible for the extensive Citation: metabolism of polyphenols thus modulating their biological activities. The aim of this Eid HM, Wright ML, Anil Kumar NV, Qawasmeh A, Hassan STS, Mocan A, review is to shed light on the composition of gut microbes, their health importance and Nabavi SM, Rastrelli L, Atanasov AG how they can contribute to diseases as well as their modulation by polyphenols and and Haddad PS (2017) Significance of polysaccharides to control obesity and diabetes. In addition, the role of microbiota in Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential improving the oral bioavailability of polyphenols and hence in shaping their antidiabetic by Medicinal Plant and Food and antiobesity activities will be discussed. Ingredients. Front. Pharmacol. 8:387. doi: 10.3389/fphar.2017.00387 Keywords: microbiota, natural products, food ingredients, obesity, metabolic diseases

Frontiers in Pharmacology | www.frontiersin.org 1 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

DEFINITION OF HUMAN MICROBIOTA Major Bacteria Colonizing Healthy Human Gut The human microbiota (microflora) refers to an aggregation of Earlier studies aiming to reveal the identity of microbiota in the a mixture of microorganisms (e.g., bacteria, fungi, archaea, and gut of healthy humans have relied on culturing the microbes viruses) that live in human tissues such as skin, uterus, lungs, from fecal samples. Bacteria constitute most of the microbes and in the gastrointestinal tract without causing pathological colonizing human gut with species belonging to Firmicutes and responses in the host (Hugon et al., 2016). Instead these Proteobacteria phyla being predominant (Eggerth and Gagnon, organisms form a symbiotic relationship with their host. In this 1933; Zubrzycki and Spaulding, 1962). To a lesser extent, species relationship, the host provides a shelter and nutrition for the belonging to other phyla such as Actinobacteria, Bacteroidetes, microbes, while the microbes provide the host with essential and Fusobacteria are also present (Eggerth and Gagnon, 1933; metabolites such as vitamin K, thiamine, biotin, folic acid, and Zubrzycki and Spaulding, 1962). In later studies, several bacterial vitamin B12, digesting polysaccharides into simpler molecules, species, mostly anaerobic, have been identified in fecal samples boosting the immunity to combat pathogens, and competing obtained from 20 healthy individuals using improved cultural with the latter for survival (Santacruz et al., 2010; D’Aimmo techniques (Moore and Holdeman, 1974; Holdeman et al., 1976). et al., 2012; LeBlanc et al., 2013). Beyond their traditional benefits, At least 400 bacterial species were suggested to colonize human recent studies have implicated microbes residing human gut gut and a total of 113 species have been fully recognized in in modulating brain development (Wang and Wang, 2016), the tested samples (Moore and Holdeman, 1974; Holdeman altering metabolic functions (Martinez et al., 2016), hormones et al., 1976); major microbes identified being summarized in and neurochemical production (Baothman et al., 2016). Some Tables 1– 5. 30 years ago, human gut microbiota was largely ignored as a Until recently, culture-based studies aimed to identify causative factor for illnesses and as a target for pharmacological bacterial species in human gut were considered to be limited in intervention. Scientists were focused mainly on finding a novel their ability to fully evaluate bacterial diversity in human gut. pathogenic bacteria residing in the gut as an underlying cause This was based on the fact that such techniques cannot recover all of illnesses and as a target for drug development (Eggerth and species residing in the human gut (Gerritsen et al., 2011). Lau and Gagnon, 1933; Dalton, 1951; Walther and Millwood, 1951). In colleagues showed that culture-enriched techniques associated recent years, there has been an increasing trend in this area with molecular profiling are alternative effective techniques to of research, and the focus has been shifted toward identifying study microbial diversity in human gut (Lau et al., 2016). microbial composition of the human gut microbiota (Figure 1), Fecal samples from two healthy donors have been cultured the factors altering this composition, and relating it to the aerobically and anaerobically in 33 different culture media pathogenesis of some diseases such as diabetes (Yamaguchi et al., creating 66 different culture conditions. Cultured samples were 2016), autism (Berding and Donovan, 2016), obesity (Valsecchi then analyzed using 16S rRNA gene sequencing. In the previous et al., 2016), and other disorders (Gondalia et al., 2012; Baothman study (Lau et al., 2016), 95% of the bacteria residing human et al., 2016). In this review, we discuss the current advances in gut has been recovered with 79 new Lachnospiraceae isolates human gut microbiota, specifically their identity and diversity being identified. Using a similar approach involving culturing within the gastrointestinal tract of healthy adults as well as fecal samples obtained from two healthy African donors under their contribution to metabolic diseases. We also review current 212 different culture conditions, 340 species belonging to seven knowledge about the effects of polyphenols and polysaccharides phyla, and 117 genera have been identified in addition to 24 on gut microbiota and their role in controlling obesity and “novel” microbes (Lagier et al., 2012). Advances in culture diabetes. conditions have proven to be effective techniques, with currently over than 1,000 microbes reported to be effectively cultured (Rajilic-Stojanovic and de Vos, 2014). These microbes cluster IDENTITY OF MICROBES COLONIZING in four main phyla with 450 species in Firmicutes, 214 in HUMAN GUT Proteobacteria, 164 in Actinobacteria, and 99 in Bacteroidetes (Rajilic-Stojanovic and de Vos, 2014). Collectively, these culture- Microbes (bacteria, archaea, fungi, virus) colonizing human gut based studies indicated that human gut is a complex ecological establish a complex ecosystem with current evidences confirming system colonized by thousands of microbes which are quite large diversity in their number and identity throughout the whole variable and diverse in-term of their quantity and identity. gastrointestinal tract (Hugon et al., 2016). It is now accepted Recent studies involving state-of-the-art techniques such that each individual hold a unique set of microbes (Callaway, as 16S rDNA gene, metagenomic sequencing, and molecular 2015) whose composition is highly affected by many factors fingerprinting have rapidly increased our knowledge about the such as ethnicity, age, environment, and diet (Ursell et al., identity of the microbes residing in our gut (Hayashi et al., 2012; Yatsunenko et al., 2012). The exact composition of gut 2002; Knapp et al., 2010; Qin et al., 2010). These studies microbiota seems far from being fully identified in view of fast not only confirmed the identity of the microbes established advances in “OMICS” techniques as well as improved culture by cultural techniques, but have also confirmed the incidence conditions allowing for identification of new sets of bacteria, on “novel” microbes never detected by culture techniques. archaea, fungi, and viruses, their reclassification or renaming of Authors characterized several “novel” microbes belonging to already taxonomically known microbes (Hugon et al., 2016). Clostridium genus in fecal samples obtained from three healthy

Frontiers in Pharmacology | www.frontiersin.org 2 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

FIGURE 1 | Number of publications related to the human gut microbiota in the last decade, per year. Data were obtained by searching Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) database using the term “human gut microbiota” on 4th November 2016.

Japanese individuals by using 16S rDNA libraries and culture- to Paenibacillaceae, Planococcaceae, Bacillaceae, and based techniques (Hayashi et al., 2002). In 2004, Akkermansia Staphylococcaceae, and Lactobacillales which includes genera muciniphila a novel mucin-degrading bacterium was also belonging to Aerococcaceae, Carnobacteriaceae, Lactobacillaceae, identified from a healthy human volunteer using 16S rRNA- Leuconstocaceae, Lactococccaceae, and Streptococcaceae.A dependent approaches (Derrien et al., 2004). A. muciniphila third class called Erysipelotrichales (e.g., Dielma fastidiosa) is a Gram-negative bacterium that resides in the mucus layer has been reported to present in human gut (Ramasamy et al., and constitutes 3–5% of gut microbiota and is thus considered 2013). to be the most abundant mucus-degrading bacteria in healthy humans (Schneeberger et al., 2015). Interestingly, the abundance Proteobacteria Phylum of A. muciniphila was found to decrease in obese and diabetic Proteobacteria phylum (Table 2) comprises highly diverse Gram- animals following high-fat diet feeding as well as in obese and negative microbes colonizing the GIT of healthy adults. It diabetic human subjects (Schneeberger et al., 2015). In larger contains five major classes, α, β, γ, δ, and ε Proteobacteria scale studies (Qin et al., 2010; Human Microbiome Project with γ-class dominating other classes (Shin et al., 2015). Consortium, 2012), the diversity of the microbes in human gut Members of the phylum Proteobacteria, mostly belonging was examined using metagenomic analysis. Species belonging to to γ-proteobacteria, have a low abundance in the gut of Firmicutes, Actinobacteria, Bacteroides, and Proteobacteriaphyla healthy humans (Shin et al., 2015). The γ-proteobacteria were reported (Tables 1–4). However, other species belonging to constitute the most diverse group of bacteria in the phylum Tenercutes, Spirochaetes, Cyanobacteria, and Verrucomicrobia Proteobacteria with six orders and nine families included. phyla were reported to be present but at lesser densities (Human Several members in Aeromonadaceae and Vibreonaceae have Microbiome Project Consortium, 2012). been considered as pathogens detected in human intestine (Janda and Abbott, 1998, 2010; Hou et al., 2011). The γ-proteobacteria Firmicutes Phylum contain several genera which belong to Enterobacteriaceae, Firmicutes phylum (Table 1) represents the most diverse Pasteurellaceae Succinivibrionaceae, Pseudomonadaceae, and and the largest group of microbes making up 60–80% Moraxellaceae families. Many species of Enterobacteriaceae are of the total microbes colonizing the GIT of healthy a normal part of the gut flora found in the intestines of adults. Firmicutes include Gram-positive species with few humans with their intensity increasing with age (Hopkins exceptions such as Faecalibacterium prausnitzii (Duncan et al., 2001). Escherichia coli is one of the most important et al., 2002) previously known as Fusobacterium prausnitzii species colonizing the healthy human gut. The healthy human in the phylum Fusobacteria, and Christensenella minuta gut contains non-harmful strains of E. coli. Several other (Morotomi et al., 2012), C. massiliensis (Ndongo et al., strains of E. coli have been associated with the outbreaks of 2016b), and C. timonensis (Ndongo et al., 2016a). Firmicutes diarrhea in children (Fagundes Neto et al., 1979; Bratoeva et al., phylum is classified into two main classes, Clostridia 1994). which includes the genera belonging to Christensenellaceae, The class δ-proteobacteria includes a branch of Clostridiaceae, Eubacteriaceae, Lachnospiraceae, Peptococcaceae, predominantly aerobic sulfate-reducing bacteria that belongs to Peptostreptococcaceae, Ruminococcaceae, and Veillonellaceae Desulfovibrionaceae family (Beaumont et al., 2016). The interest families and Bacilli which are divided into two main in this class was due to the ability of its species to generate orders; Bacillales which includes the genera belonging the highly toxic hydrogen sulfide (H2S) molecules as part of

Frontiers in Pharmacology | www.frontiersin.org 3 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 1 | Firmicutes phylum (class, order, family) and major species constituting the microbiota in healthy human gut.

Class Order Family Species References

Clostridia Clostrdiales Peptostreptococcaceae Peptostreptococcus productus I Holdeman et al., 1976 Peptostreptococcus productus II Moore and Holdeman, 1974; Holdeman et al., 1976 Anaerococcus senegalensis Lagier et al., 2012 Ruminococcaceae Ruminococcus AJ Moore and Holdeman, 1974; Holdeman et al., 1976 Ruminococcus albus Moore and Holdeman, 1974; Holdeman et al., 1976 Ruminococcus obeum Holdeman et al., 1976 (Blautia obeum) Lawson and Finegold, 2015 Ruminococcus torques Moore and Holdeman, 1974; Holdeman et al., 1976 Ruminococcus bromii Moore and Holdeman, 1974; Holdeman et al., 1976 Ruminococcus massiliensis Lagier et al., 2012 Eubacteriaceae Eeubaterium limosum Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium aerofaciens Moore and Holdeman, 1974; Holdeman et al., 1976 (Collinsella aerofaciens) Kageyama et al., 1999 Eubacterium aerofaciens II Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium aerofaciens III Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium siraeum Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium rectile I Moore and Holdeman, 1974 Eubacterium rectale II Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium rectale III-H Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium rectale IV Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium rectale III-F Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium eligens Holdeman et al., 1976 Eubacterium biforme Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium formicigenerans Holdeman et al., 1976 Eubacterium ballii Holdeman et al., 1976 Eubacterium ventriosum I Moore and Holdeman, 1974; Holdeman et al., 1976 Eubacterium formicigenerans Moore and Holdeman, 1974 ( Dorea formicigenerans) Taras et al., 2002 Clostridiaceae Clostridium leptum Holdeman et al., 1976 Clostridium ramosum I Holdeman et al., 1976 Clostridium orbisindens Hayashi et al., 2002 Clostridium senegalense Lagier et al., 2012 Faecalibacterium prausnitzii Duncan et al., 2002 Dorea longicatena Qin et al., 2010 Lachnospiraceae Coprococcus eutactus Moore and Holdeman, 1974; Holdeman et al., 1976 Coprococcus comes Moore and Holdeman, 1974 Coprococcus catus Moore and Holdeman, 1974 Christensenellaceae Christensenella minuta Morotomi et al., 2012 Christensenella timonensis Ndongo et al., 2016a Christensenella massiliensis Ndongo et al., 2016b

Bacilli Lactobacillales Lactobacillaceae Lactobacillus acidophilus Rajilic-Stojanovic and de Vos, 2014 Lactobacillus leichmannii Holdeman et al., 1976 Lactobacillus salivarius Rajilic-Stojanovic and de Vos, 2014 Lactobacillus bulgaricus Rajilic-Stojanovic and de Vos, 2014 Lactobacillus casei Moore and Holdeman, 1974 Lactobacillus rhamnosus Rajilic-Stojanovic and de Vos, 2014 Lactobacillus plantarum Rajilic-Stojanovic and de Vos, 2014 Lactobacillus fermentum Moore and Holdeman, 1974 Streptococcacaea Streptococcus dysgalactiae Lagier et al., 2012

(Continued)

Frontiers in Pharmacology | www.frontiersin.org 4 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 1 | Continued

Class Order Family Species References

Streptococcus agalactiae Lagier et al., 2012 Streptococcus gordonii Lagier et al., 2012 Bacillales Bacillaceae Bacillus massiliosenegalensis Lagier et al., 2012 Bacillus timonensis Lagier et al., 2012 Oceanobacillus massiliensis Lagier et al., 2012 Palanococcaceae Kurthia massiliensis Lagier et al., 2012 Kurthia senegalensis Lagier et al., 2012 Kurthia timonensis Lagier et al., 2012 Paenibacillaceae Paenibacillus senegalensis Lagier et al., 2012 Erysipelotrichai Erysipelotrichales Erysipelotrichaceae Dielma fastidiosa Lagier et al., 2012; Ramasamy et al., 2013

their metabolic pathways. Overproduction of H2S has been Bacteroidetes Phylum associated with pathogenesis of ulcerative colitis and colon Bacteroidetes phylum (Table 4) includes several large classes cancer (Beaumont et al., 2016). of Gram-negative, non-spore forming, anaerobic or aerobic, The class β-Proteobacteria contains species belonging to and rod-shaped bacteria that are widely distributed in the Neisseria genera (Table 2). Neisseria meningitis and Neisseria environment and in the human guts (Belizário and Napolitano, gonorrhea are amongst the most studied species classified 2015). By far, species in the class Bacteroidia have been most within this group (Corless et al., 2001; Unemo et al., extensively studied due to their relevance to human metabolic 2014). Both species are Gram-negative coccoid bacteria, once processes. These species play a vital role in metabolizing complex thought to be restricted to humans and are part of the molecules such as proteins and polysaccharides such as cellulose, microflora of the upper respiratory and genito-urinary tracts pectin and xylans into simpler molecules used as source of energy but have not yet been recognized in the intestine. Despite (Wexler, 2007; Xu et al., 2007; Sakamoto and Ohkuma, 2012). being considered as part of the normal intestinal flora, Bacteroidia colonizing human gut include species clustered Neisseria subflave has been linked to meningitis (Baraldes in Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, and et al., 2000). Sutterellaceae species are frequently detected in Rikenellaceae families. They are symbiotic and diverse bacteria human gut. They have received much attention in recent year making up a substantial portion of the normal flora residing because their density is reported to increase in inflammatory in lower GIT (1010–1011 cells per gram of human feces; bowel diseases and in children suffering from autism and Holdeman et al., 1976). Other bacterial species belonging to down-syndrome (De Angelis et al., 2013; Hiippala et al., classes sphingobacteria and flavobacteria have occasionally been 2016). detected in healthy human gut (Lagier et al., 2012), however their significance in the gut has yet to be demonstrated. Actinobacteria Phylum Actinobacteria phylum (Table 3) constituting healthy human gut Fusobacteria Phylum microbiota includes diverse Gram-positive species that comprise Fusobactera phylum (Table 5) includes Gram-negative, non- three orders and 19 families. The Bifidobacterium species are sporeforming, anaerobic bacilli frequently detected in human gut one of the major genera of bacteria that are frequently detected (Walter et al., 2002). This phylum includes species belonging exclusively in human gut and have been isolated from infant feces to Fusobacteriaceae and Leptotrichiaceae families. Species within since 1900 (Rajilic-Stojanovic et al., 2007). Some Bifidobacterium Fusobacteriaceae were considered to be limited to the oral cavity species are critical to the health of the gut and are now considered until 1966 when it was shown that they could be detected in as essential constituents of the probiotics used in the treatment fecal samples (Van Houte and Gibbons, 1966). Fusobacteriaceae of inflammatory bowel disease with no obvious side effects species appear to be directly related to the health of the (Ghouri et al., 2014). In contrast to Bifidobacteriales species, gut. Their density increases in inflammatory diseases such as the Actinomycetales species, despite being a highly diverse appendicitis (Swidsinski et al., 2012), ulcerative colitis (Rajilic- group of bacteria, have a relatively low abundance in healthy Stojanovic et al., 2013) and colon cancer (Kostic et al., 2012). human gut: (102–103) cells/g of fecal sample (Hoyles et al., Leptotrichiaceae species appears to be detected mainly in human 2012). Amongst most detected genera are Corynebacterium and elderly gut (Hayashi et al., 2005) and female reproductive system Propionibacterium (Eggerth, 1935; Moore and Holdeman, 1974; (Thilesen et al., 2007). Holdeman et al., 1976). Species in Propionibacterium are capable of producing propionic acid from lactic acid and also vitamin Archaea, Viruses, and Fungi Colonizing B12 (Kiatpapan and Murooka, 2002), making them an ideal Healthy Human Gut species to be included in probiotics (Kiatpapan and Murooka, Healthy human gut microbiota includes archaea, fungi, and 2002). viruses as consistent residents (Parfrey et al., 2011; Lloyd-Price

Frontiers in Pharmacology | www.frontiersin.org 5 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 2 | Proteobacteria phylum (class, order, family) and major species constituting the microbiota in healthy human gut.

Class Order Family Species References

α-Proteobacteria Rhizobiales Hyphomicrobiaceae Gemmiger formicilis Holdeman et al., 1976 Methylobacteriaceae Microvirga massiliensis Caputo et al., 2016 Methylobacterium adhaesivum Kaakoush et al., 2012 Methylobacterium hispanicum Kaakoush et al., 2012 Methylobacterium radiotolerans Lagier et al., 2012

β-Proteobacteria Burkholderiales Alcaligenaceae Alcaligenes faecalis Oxalobacteriaceae Herbaspirillum massiliensis Lagier et al., 2012 Sutterellaceae Parasutterella excrementihominis Nagai et al., 2009 Sutterella wadsworthensis Wexler et al., 1996 Parasutterella secunda Morotomi et al., 2011 Neisseriaceae Neisseria flavascens Lagier et al., 2012 Neisseria subflava Wang et al., 2005 Neisseria preflava Lagier et al., 2012 Neisseria mucosa Lagier et al., 2012 Neisseria cinera Lagier et al., 2012

γ-Proteobacteria Aeromondales Succinivibrionaceae Succinatimonas hippie Morotomi et al., 2010 Anaerobiospirillum succiniciproducens Morotomi et al., 2010 Enterobacteriales Enterobacteriaceae Escherichia coli Moore and Holdeman, 1974 Escherichia fergusonii Lagier et al., 2012 Enterobacter massiliensis Lagier et al., 2012 Enterobacter cloaceae Lagier et al., 2012 Shigella sonnei Hooda et al., 2012 Pasteurellales Pasteurellaceae Haemophilus parainfluenzae Lagier et al., 2012 Pseudomonadales Moraxellaceae Morexella osloensis Lagier et al., 2012 Actinobacter radioresistens Lagier et al., 2012 Actinobacter calcoaceticus Lagier et al., 2012 Actinobacter septicus Lagier et al., 2012 Pseudomonadaceae Pseudomonas aeruginosa Lagier et al., 2012 Pseudomonas oleovorans Lagier et al., 2012 Pseudomonas stutzeri Lagier et al., 2012

δ-Proteobacteria Desulfovibrionales Desulfovibrionaceae Desulfovibrio desulfuricans Newton et al., 1998 Desulfovibrio fairfieldensis Loubinoux et al., 2002 Desulfovibrio piger Loubinoux et al., 2002 Bilophla wadsworthia Baron et al., 1989

ε-Proteobacteria Campylobacterales Campylobacteraceae Halicobacteraceae

et al., 2016; Rehman et al., 2016), even though in some cases M. stadtmaniae, and M. luminyensis, are the most prevalent at low densities. A small number of archaeal genera have been (Rajilic-Stojanovic and de Vos, 2014; Horz, 2015) in the healthy identified in the healthy human microbiota, primarily in the gut. gut. M. smithii in particular, has been found to be well-adapted Historically, archaea were classified as bacteria with the name to inhabit the human gut. These species are implicated in (archaebacteria) before being reclassified in a specific domain optimizing the digestion process of dietary polysaccharides in (Woese et al., 1990; Pace, 2006), since they have characteristic association with other microbes (Samuel et al., 2007) and they features unique enough to separate them from bacteria and are capable of producing methane (methanogenes) from CO2 2 Eukaryota domains (Cavicchioli, 2011). In total, eight archaeal and H2. Their abundance in infants is relatively low (10 – species have been associated with the human GIT (Rajilic- 106 cell/g of fecal sample) and increases during adulthood Stojanovic and de Vos, 2014). Species of the Methanobrevibacter reaching up to 1010 cells/g fecal samples. Such changes in genus, namely; Methanobervibacter smithii, M. ruminantium, densities explain the absence of methane gas, as detected by a

Frontiers in Pharmacology | www.frontiersin.org 6 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 3 | Actinobacteria phylum (class, order, family) and major species constituting the microbiota in healthy human gut.

Class Order Family Species References

Actinobacteria Bifidobacteriales Bifidobacteriaceae Bifidobacterium adolescentis Holdeman et al., 1976; Ramirez-Farias et al., 2009; Duranti et al., 2016 Bifidobacterium infantis Moore and Holdeman, 1974; Holdeman et al., 1976; Hayashi et al., 2002 Bifidobacterium longum Moore and Holdeman, 1974; Holdeman et al., 1976 Bifidobacterium breve Moore and Holdeman, 1974 Bifidobacterium bifidum Hayashi et al., 2002 Actinomycetales Actinomycettaceae Arcanobacterium haemolyticum Lagier et al., 2012 Actinomyces odontolyticus Lagier et al., 2012 Dermabacteraceae Dermabacter hominis Lagier et al., 2012 Corynebacteriacaea Senegalemassilia anaerobia Lagier et al., 2012 Corynebacterium appendicis Lagier et al., 2012 Corynebacterium glaucum Lagier et al., 2012 Corynebacterium aurimucosum Lagier et al., 2012 Corynebacterium freneyi Lagier et al., 2012 Corynebacterium glucuronolyticum Lagier et al., 2012 Corynebacterium minutissimum Lagier et al., 2012 Corynebacterium propinquum Corynebacterium mucifaciens Lagier et al., 2012 Corynebacterium tuberculostearicum Lagier et al., 2012 Corynebacterium coyleae Lagier et al., 2012 Micrococcacaea Rothia aeria Lagier et al., 2012 Rothia dentocariosa Lagier et al., 2012 Rothia mucilaginosa Lagier et al., 2012 Micrococcus luteus Lagier et al., 2012 Kocuria halotolerans Lagier et al., 2012 Kocuria kristinae Lagier et al., 2012 Kocuria marina Lagier et al., 2012 Kocuria palustris Lagier et al., 2012 Kocuria rhizophila Lagier et al., 2012 Dermacoccus nishinomiyanensis Lagier et al., 2012 Arthrobacter castelli Lagier et al., 2012 Arthrobacter oxydans Lagier et al., 2012 Microbacteriaceae Microbacterium oleivorans Lagier et al., 2012 Microbacterium paraoxydans Lagier et al., 2012 Microbacterium phylosphaerae Lagier et al., 2012 Microbacterium schleigeri Lagier et al., 2012 Microbacterium folliorum Lagier et al., 2012 Microbacterium gubbeenense Lagier et al., 2012 Agrococcus jenensis Lagier et al., 2012 Propionibacteriaceae Propionibacterium acnes Moore and Holdeman, 1974; Holdeman et al., 1976 Propionibacterium avidum Eggerth, 1935 Nocardioidaceae Aeromicrobium massiliense Lagier et al., 2012 Rhodococcus equi Lagier et al., 2012 Rhodococcus rhodocrous Lagier et al., 2012 Gordoniaceae Gordonia rubripertincta Lagier et al., 2012 Dietziaceae Dietzia natrolonimnaea Lagier et al., 2012 Dietzia cinnamea Lagier et al., 2012 Dietzia maris Lagier et al., 2012 Brevibacteriaceae Brevibacterium senegalense Lagier et al., 2012 Brevibacterium linens Lagier et al., 2012

(Continued)

Frontiers in Pharmacology | www.frontiersin.org 7 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 3 | Continued

Class Order Family Species References

Brevibacterium epidermidis Lagier et al., 2012 Brevibacterium halotolerans Lagier et al., 2012 Brevibacterium iodinosis Lagier et al., 2012 Brevibacterium casei Lagier et al., 2012 Brevibacterium ravenspurgense Lagier et al., 2012 Cellulomonadaceae Cellulomonas massiliensis Lagier et al., 2012 Cellulomonas composti Lagier et al., 2012 Cellulomonas denverensis Lagier et al., 2012 Cellulomonas parahominis Lagier et al., 2012 Cellulosimicrobium cellulans Lagier et al., 2012 Sanguibacteraceae Timonella senegalensis Lagier et al., 2012 Streptomycetaceae Streptomyces missionensis Lagier et al., 2012 Promicromonosporaceae Promicromonospora flava Lagier et al., 2012 Micromonosporaceae Micromonospora aurantiaca Lagier et al., 2012 Intrasporangiaceae Kytococcus schroeteri Lagier et al., 2012 Coriobacteriales Coriobacteriacaea Colinsella aerofaciens Lagier et al., 2012 Propionibacterium acnes Moore and Holdeman, 1974; Lagier et al., 2012 Propionibacterium avidum Eggerth, 1935 Propionibacterium granulosum Finegold et al., 1974; Lagier et al., 2012 Mycobacteriaceae Mycobacterium abcsessus Lagier et al., 2012 Mycobacterium fortuitum Lagier et al., 2012

breath test, during infancy in contrast to adulthood (Gaci et al., (Adenoviridae), polyomavirus (Polyomaviridae), gyrovirus 2014). (Circoviridae), and some other unclassified viruses Archaeal science appears to be in its early stages. Unlike were generally detected in fecal samples (Wylie et al., bacteria, archaeal species are largely ignored as a topic in 2014). microbiology, possibly due to the lack of appropriate genomic A better understanding of human virome composition tools to reveal their existence and their diversity (Horz, 2015). and dynamics should confirm that it is an important Accordingly, it is quite likely that the archaeal domain represents factor contributing to human health (Scarpellini et al., a diverse community with several yet unknown taxa, waiting to 2015). Indeed, several recent studies have implicated gut be identified. Although, some archaeal species (methanogens) virome in regulating/stabilizing their host bacterial species appears to be associated with gut inflammatory diseases, and subsequently maintaining microbial diversity in the including constipation, the question arises as to whether it is gastrointestinal tract (Minot et al., 2011; Abeles and Pride, 2014; necessary to identify all taxa. Even if they are rare and/or Scarpellini et al., 2015). present only in very low abundance, their precise role in In addition, several fungal species have been reported to disease development remains unknown (Gaci et al., 2014; Horz, colonize healthy human gut, even if at low amounts (Ott et al., 2015). 2008; Sokol et al., 2016). The most prevalent fungal species Many viral species have been reported to colonize the detected in the healthy human gut are clustered into three phyla; healthy human gut system forming a symbiotic relationship Ascomycota, Basidiomycota, and Zygomycota. Candida albicans with their bacterial (bacteriophages) and human hosts. These and Candida rugosa have routinely been detected in human gut viruses constitute the so called “human gut virome” (Zou (Ott et al., 2008; Sokol et al., 2016). Most Candida species under et al., 2016). Each individual holds a unique viral profile, normal conditions form symbiotic/commensal relationships with highlighting the high interpersonal variability of the healthy the host. However, when host environmental conditions favor human gut virome (Minot et al., 2011; Scarpellini et al., 2015). the outgrowth of C. albicans, excessive colonization can lead to The human virome includes viruses from seven families, namely infection and invasion of host tissues (Ott et al., 2008; Sokol et al., Herpesviridae, Polyomaviridae, Papillomaviridae, Adenoviridae, 2016). Anelloviridae, Parvoviridae, and Circoviridae. Not all families have been detected in healthy human gut (Wylie et al., 2014). DIVERSITY ALONG HUMAN GUT In a large scale metagenomic study involving 102 healthy individuals, roseolovirus (Herpesviridae), alphapapillomavirus The human gut is colonized by higher numbers of bacteria and gammapapillomavirus (Papillomaviridae), mastadenovirus and more diverse species compared to other parts of the body

Frontiers in Pharmacology | www.frontiersin.org 8 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 4 | Bacteroidetes phylum (class, order, family) and major species constituting the microbiota in healthy human gut.

Class Order Family Species References

Bacteroidia Bacteroidales Bacteroidaceaae Bacteroides thetiotaomicron Moore and Holdeman, 1974; Holdeman et al., 1976; Xu et al., 2003 Bacteroides fragilis Moore and Holdeman, 1974; Holdeman et al., 1976 Bacteroides clostridiiformis Moore and Holdeman, 1974; Hayashi et al., 2002 Bacteroides vulgatus Moore and Holdeman, 1974; Holdeman et al., 1976 Bacteroides distasonis Moore and Holdeman, 1974; Holdeman et al., 1976 (parabacteroides distasonis) Sakamoto and Benno, 2006 Bacteroides capillosus Holdeman et al., 1976 Bacteroides eggertbin Holdeman et al., 1976 Bacteroides uniformis Hayashi et al., 2002 Bacteroides stercoris Hayashi et al., 2002 Bacteroides eggerthii Hayashi et al., 2002 Bacteroides goldsteinii Moore and Holdeman, 1974 (Parabacteroides goldsteinii) Sakamoto and Benno, 2006 Bacteroides merdae Moore and Holdeman, 1974 (parabacteroides merdae) Sakamoto and Benno, 2006 Bacteroides intestinalis Qin et al., 2010 Parabacteroides distastonis Sakamoto and Benno, 2006 Parabacteroides johnsonii Lagier et al., 2012 Parabacteroides merdae Sakamoto and Benno, 2006 Parabacteroides goldsteinii Sakamoto and Benno, 2006 Porphyromonadacaea Gabonibacter massiliensis Mourembou et al., 2016 Porphyromonas somerae Lagier et al., 2012 Prevotellaceae Prevotella copri Hayashi et al., 2007 Prevotella stercorea Hayashi et al., 2007 Prevotella oris Hasegawa et al., 1997 Prevotella bivia Lagier et al., 2012 Prevotella melalingenica Lagier et al., 2012 Prevotella nigrescens Lagier et al., 2012 Prevotella veroralis Lagier et al., 2012 Prevotella amnii Knapp et al., 2010 Rikenellaceae Alistipes senegalensis Lagier et al., 2012 Alistipes timonensis Lagier et al., 2012 Alistipes shahii Song et al., 2006; Lagier et al., 2012 Alistipes obesiensis Lagier et al., 2012 Alistipes onderdonkii Song et al., 2006 Alistipes pytredinis Hayashi et al., 2002

Sphingobacteria Sphingobacteriales Sphingobactereaceae Sphingobacterium multivorum Lagier et al., 2012

Flavobacteria Flavobacterialis Flavobacteriaceae Flavobacterium lindanitolerans Lagier et al., 2012

(Quigley, 2013). The microbial composition of the gut flora varies represents ∼60% of fecal dry mass (Stephen and Cummings, along the gut (Table 6), with stomach and small intestine having 1980). Fungi, archaea, and viruses are also present in the gut relatively lower microbial diversity (Guarner and Malagelada, flora, but less is known about their activities (Lozupone et al., 2003; O’Hara and Shanahan, 2006). In contrast, the colon 2012). is densely colonized by microbes reaching up to 1012 cells per gram of intestinal content (O’Hara and Shanahan, 2006). Stomach Flora There are between 300 and 1,000 different bacterial species, Healthy human stomach has no longer been considered as a but the vast majority of bacteria (99%) come from 50 to 60 “sterile organ” since the discovery of H. pylori (Marshall and species (Guarner and Malagelada, 2003; Rajilic-Stojanovic et al., Warren, 1984). It is rather now considered as a harbor for many 2007). Because of their abundance in the intestine, bacteria bacterial species, dominated by five major phyla: Firmicutes,

Frontiers in Pharmacology | www.frontiersin.org 9 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

TABLE 5 | Fusobacteria phylum (class, order, family) and major species constituting the microbiota in healthy human gut.

Class Order Family Species References

Fusobacteria Fusobacteriales Fusobacteriaceae Fusobacterium prausnitzii Moore and Holdeman, 1974; Holdeman et al., 1976; Miquel et al., 2013 Fusobacterium russii Moore and Holdeman, 1974; Holdeman et al., 1976 Fusobacterium varium Holdeman et al., 1976; Walter et al., 2002 Fusobacterium gonidiaformans Walter et al., 2002 Fusobacterium naviforme Walter et al., 2002 Fusobacterium mortiferum Holdeman et al., 1976 Fusobaccterium nucleatum Holdeman et al., 1976 Fusobaccterium peridonticum Roberfroid et al., 2010 Leptotrichiaceae Leptotrichia buccalis Vaahtovuo et al., 2005 Leptotrichia amnionii Rajilic-Stojanovic and de Vos, 2014

TABLE 6 | Diversity of microbes along the human gut.

Stomach Duodenum Jejunum Proximal Distal ilium Colon References ilium pH 1.4–5 4.5–6.1 4.7–6.5 6.3–7.4 6.8–7.9 5.3–6.7 Evans et al., 1988 Food passage time (h) 2–6 3–5 10–20 Microbial density /g −102 102 102 103 108 1012 O’Hara and Shanahan, sample 2006 Major genera Helicobacter pylori Streptococcus Streptococcus Streptococcus Streptococci Bacteroides Davis, 1996; Gaci Lactobacillus Lactobacillus Lactobacillus Lactobacilli Bifidobacterium et al., 2014; Scarpellini Streptococcus Bacteroides Eubacterium, et al., 2015 Clostridium bifidobacteria Peptostreptococcus Staphylococcus Virus Lactobacillus Fungi Peptostreptococcu Archaea Number of phylotypes NA NA 22 NA 33 37 Wang et al., 2005

Bacteroidites, Actinobacteria, Fusobacteria, and Proteobacteria. what extent H. pylori infection or stomach cancer affects the Generally, the healthy human stomach is dominated by composition of stomach microbiota and whether restoring Prevotella, Streptococcus, Veillonella, Rothia, and Haemophilus stomach biota, either naturally or pharmacologically, can (Bik et al., 2006; Zilberstein et al., 2007). Characterizing healthy modulate the outcome of an H. pylori infection or cancer stomach microbiota has come from studies involving gastric progression (Wroblewski and Peek, 2016). biopsies and stomach juices collected from individuals routinely performing upper gastrointestinal endoscopy for dyspepsia (Li Intestinal Flora et al., 2009; Engstrand and Lindberg, 2013). Using a small Most of the studies describing gut microbial composition in subunit 16S rDNA clone library approach (Bik et al., 2006), health adults have usually involved fecal samples, representing 128 phylotypes have been shown to colonize the stomach, the diversity of the microbes present in the large intestine coming from the five major phyla mentioned above. Essentially (Finegold et al., 1974; Moore and Holdeman, 1974; Holdeman similar findings have been reported by other researchers et al., 1976). The small intestine, however, is more acidic, has despite differences in techniques (Delgado et al., 2013) and the higher levels of oxygen, less transit time, and has effective ethnic background of biopsy donors (Li et al., 2009; Delgado immune-cell-mediated antimicrobial factors compared with the et al., 2013; Engstrand and Lindberg, 2013), suggesting that colon (Keshav, 2006). Such physiological variations promote some homogeneity may exist in the composition of stomach less microbial diversity in small intestine compared with colon. microbiota. Accordingly, only fast growing facultative anaerobes, which The contribution of stomach microbiota to disease tolerate the bactericidal effects of bile acid and effectively compete pathogenesis has not yet been fully explored, although an for carbohydrate, will dominate this part of the gut (Zoetendal alteration in the density of Firmicutes phylum, particularly et al., 2012). There are limited studies aimed to assess small the Streptococcus and Prevotella genera, has been reported intestinal microbial diversity (Hartman et al., 2009; Zoetendal in patients with H. pylori infection and stomach cancer et al., 2012). This is partly due to the technical difficulties in (Wroblewski and Peek, 2016). It remains pivotal to know to collecting samples for analysis.

Frontiers in Pharmacology | www.frontiersin.org 10 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Small intestine microbiota has been examined in three In other words, differential gene expression in host cells allow for different anatomical locations, namely jejunum, ileum, and distal specific types of bacteria to colonize one individual over another, ileum. Despite the fact that each part is characterized by its own and the way a cell responds to bacteria (or the community of microbial composition, it appears that the profile of the jejunum microbes present) may vary depending on the host’s genetic is closely related to that of the stomach; with Bacilli, mainly of make-up. However, environment and diet appear to be the the Streptococcaceae species, dominating this section (50–70%) strongest drivers of microbiota composition, with some of the (Wang et al., 2005; Zoetendal et al., 2012). Even in elderly, observed variance attributable to host genetics (Richards et al., moving along the small intestine toward the colon, the intensity 2016). of Bacilli species in the ileum and distal ileum drop remarkably to reach 20 and 5%, respectively (Hayashi et al., 2005; Zoetendal et al., 2012). Instead Clostridia species such as IX, XIVb XIVa, Gut Microbiota and Human Health and IV form up to 30% of the microbiome, while Bacteroidetes Despite inter-individual differences in the structure and diversity species occupy a proportion of 49% at these locations (Wang of the human gut microbiome, the microbial metabolic and et al., 2005; Zoetendal et al., 2012). functional pathways remain stable among healthy individuals (Human Microbiome Project Consortium, 2012). The human gut microbiome encodes at least 10-fold more genes than the human HUMAN GUT MICROBIOTA IN HUMAN genome and functional redundancy among some of these genes HEALTH AND DISEASE allow different microbes to create individualized communities that will carry out the same functions to maintain homeostasis There is increasing evidence that differences in the structure, and a symbiotic relationship with the human host (Ley et al., function, and diversity of the human gut microbiota are 2006; Qin et al., 2010). The functional redundancy is important associated with states of human health and disease. for maintaining a favorable environment within the gut to ensure survival of the bacteria, while also contributing to human Establishment of Gut Microbes metabolism and health (Parekh et al., 2014). This is significant The first 2 years of life mark a dynamic period in which the gut because the bacteria present in gut microbiome communities microbiome builds from the initial microbial repository at birth help liberate carbohydrates and other nutrients from the diet that and adjusts until the composition and function are more like that could otherwise not be utilized by the human host (Larsbrink of an adult (Koenig et al., 2011). The type of birthing delivery et al., 2014). For example, certain species of Bacteriodetes can strongly influences which microbes are present upon the initial metabolize xyloglucans, a complex carbohydrate found in dietary establishment of an individual’s gut microbiota. Infants born fiber that contributes to human’s carbohydrate intake. At least vaginally develop gut microbiota that are more similar to their one of the taxa capable of this type of metabolism is consistently mothers than those born via cesarean section; this also conferring reported in studies evaluating gut microbiota (Larsbrink et al., some functional differences. For example, gut microbiota in 2014). Since products of gut microbe metabolism, like that of infants born vaginally tend to express a lower proportion of xyloglucans, contribute to the symbiotic relationship between antibiotic resistance genes (Bäckhed et al., 2015). The developing host and microbe, there has been increasing interest in how gut microbiota is strongly influenced by the infant’s diet and life the microbes and their metabolic products contribute to human events. Over time, the infant begins harboring microbes capable health and disease. of digesting complex sugars and starch (Koenig et al., 2011; As mentioned, Firmicutes and Bacteroidetes are the most Bäckhed et al., 2015). As more types of foods are introduced into predominant phyla in the human gut and affect the production the infant’s diet, the bacterial diversity in the gut increases. For of short-chain fatty acids (Rosenbaum et al., 2015). Short-chain infants who are breastfed, the discontinuation of breastfeeding fatty acids (SCFA) produced from indigestible carbohydrates appears to be the strongest factor driving the change in gut by gut microbes are used as energy by various human tissues microbiota structure from the less diverse infant microbiome to (Rosenbaum et al., 2015). Some studies have observed that the the more diverse adult phenotype (Koenig et al., 2011; Bäckhed proportions of bacteria present in these phyla may contribute et al., 2015). to metabolic outcomes in the host, in part by altering the Host genetic signature has also been reported to contribute, amount of short-chain fatty acids produced (Turnbaugh et al., to a certain extent, to the types of microbes present within an 2006, 2009). Greater density of Bacteroidetes has been associated individual’s gut. Although, studies generally suggest that genetic with increased butyrate and propionate levels that contribute effects do not exert a strong global influence on which microbes to a healthy body weight by suppressing hunger and helping colonize the gut, monozygotic twin pairs display more similar to maintain glucose homeostasis (Lin et al., 2012). Butyrate microbiota than their dizygotic counterparts (Turnbaugh et al., produced by the gut microbes also contributes to health by 2009; Smith et al., 2013; Goodrich et al., 2014). Moreover, even providing energy for colonic epithelial cells and inhibiting if few bacterial taxa exhibit strong heritability, the strongest inflammation, particularly that induced by lipopolysaccharide are associated with clinically meaningful phenotypic differences (Cani et al., 2007; Belkaid and Hand, 2014). (Goodrich et al., 2014). Recent evidence suggests that there is A. muciniphila, is a Gram-negative bacterium of the order cross talk between the gut microbiome and host genetic signature Verrucomicrobiales. Despite containing lipopolysaccharides that results from altered gene expression (Richards et al., 2016). (LPS), a well-known endotoxin, a study by Everard et al. (2013)

Frontiers in Pharmacology | www.frontiersin.org 11 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients has demonstrated the lack of direct association between Gram- that complex disorders with metabolic components may benefit negative bacteria and gut or metabolic endotoxemia (Everard from targeted alterations in the microbiota through dietary et al., 2013). On the contrary, oligofructose administration which or supplement interventions. For this review, we will focus has been reported to restore A. muciniphila levels mitigated specifically on reviewing the microbiome literature as it relates to endotoxemia caused by HFD (Everard et al., 2013). Other metabolic syndrome. studies also reported the seemingly counterintuitive results that A. muciniphila preserves the integrity of the intestinal Overview of Metabolic Syndrome mucous and intestinal barrier function and counteracts the Metabolic syndrome is a group of factors that collectively raise deleterious effect of HFD on gut permeability despite having the risk for other chronic and acute disease processes. The greater week mucin-degrading activities (Cani et al., 2009; Belzer and the number of the risk factors an individual has, the higher the de Vos, 2012; Everard et al., 2013). One explanation is that risk for other poor health outcomes and disease such as heart this bacterium protects against inflammation through increasing attacks, stroke, and type 2 diabetes. Metabolic syndrome risk the levels of the anti-inflammatory intestinal endocannabinoids factors are closely linked with obesity and sedentary lifestyles which control gut barrier and gut peptide secretion (Everard (Alberti et al., 2009; Kaur, 2014). There are several different et al., 2013). In addition, higher levels of A. muciniphila were reports that include diagnostic criteria for metabolic syndrome associated with greater enteroendocrine L-cell activity, hence that are utilized in different areas of the world (Alberti et al., more secretion of glucagon-like peptides GLP-1 and GLP-2 2009; Kaur, 2014). Despite some minor difference in criteria, (Cani et al., 2009). Gut peptides including GLPs were reported individuals presenting with metabolic syndrome exhibit 2– to control epithelial barrier proliferation and integrity (Belzer 3 of the following characteristics: central obesity, abnormal and de Vos, 2012). It was demonstrated that A. muciniphila serum lipid levels (high triglycerides and/or low high-density controls GLP-2 secretion through increasing levels of 2- lipoprotein), high blood pressure, and elevated blood glucose oleoylglycerol (2-OG) and reduces metabolic endotoxemia levels. Some groups contain diagnostic metrics for insulin via increasing 2-arachidonoylglycerol (2-AG) levels (Everard resistance, whereas others do not since it is difficult to uncouple et al., 2013). However, the link between the enhanced from obesity (Alberti et al., 2009; Kaur, 2014). production of endocannabinoids and the beneficial effects of A. The mechanistic pathways for obesity are complex due to muciniphila needs further investigation. Other studies reported a multiplicity of genetic and lifestyle factors that contribute to that A. muciniphila levels were reduced in diseases involving weight gain, although insulin is a critical regulator of adipocyte dysfunctional intestinal barrier such as irritable bowel syndrome biology (Grundy et al., 2004). Insulin inhibits lipolysis and (IBS) and chronic granulomatous colitis (Falcone et al., 2016). stimulates glucose transport as well as triglyceride synthesis However, some authors reported contradictory results; for (Grundy et al., 2004). When lipolysis is stimulated in insulin example a Chinese MGWAS study stated that A. muciniphila resistant individuals, large amounts of circulating fatty acids did not improve mucous layer thickness (Tilg and Moschen, and inflammatory markers are released from expanded adipose 2014), while Ganesh et al. attributed exacerbated inflammation in tissue mass (Grundy et al., 2004; Afsar and Elsurer, 2014). Salmonella typhimurium-infected mice to the mucin-degrading When these processes occur consistently over time, elevations effect of A. muciniphila (Ganesh et al., 2013). Such conflicting in weight and blood sugar become apparent and begin to studies need further clarification. influence other metabolic processes (Grundy et al., 2004; In general, imbalances in the types of bacteria present in the Afsar and Elsurer, 2014). The increase in circulating free gut microbiota are thought to contribute to disease in part by fatty acid levels contributes to the development of triglyceride altering different metabolic processes and/or pathways in the reservoirs in muscle and liver, resulting in decreased glucose host. uptake in muscle, increased hepatic gluconeogenesis, and increased blood cholesterol and triglyceride levels which may Gut Microbiota and Disease also contribute to rising blood pressure (Afsar and Elsurer, Differences in the composition of the gut microbiota in 2014). The resultant pro-inflammatory and pro-thrombotic humans that relate to disease have been reported for several states increase the risk for cardiovascular disease and type 2 conditions including, but not limited to, cardiovascular disease diabetes (Afsar and Elsurer, 2014). Since the aforementioned (Holmes et al., 2008; Wang et al., 2011), type 2 diabetes components of metabolic syndrome overlap to some degree (Larsen et al., 2010), and obesity (Turnbaugh et al., 2009). mechanistically, similar overlap in differences in microbiota have Interest in studying the human gut microbiota related to been reported based on metabolic syndrome diagnostic criteria disease has increased, in part due to the fact that it appears (Rial et al., 2016). to be highly influenced by interventions that ameliorate symptoms or disease such as medications and diet. For example, Gut Microbiota and Obesity individuals that eat red meat exhibit greater levels of the gut Diagnostic criteria for obesity, particularly central or abdominal metabolite trimethylamine-N-oxide (TMAO) than non-meat obesity, vary by guidelines and populations being assessed. eaters. Importantly, TMAO is associated with increased plaque Despite differences in diagnostic cutoffs determining obesity, formation in arteries (Koeth et al., 2013; Tang et al., 2013). several research groups have reported differences in gut The fact that products from microbial metabolism play an microbiota related to body weight (Turnbaugh et al., 2009). integral role in many metabolic pathways of the host, suggests Some of the first ground breaking studies investigating the gut

Frontiers in Pharmacology | www.frontiersin.org 12 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients microbiota in humans sought to evaluate the relationship with triglyceride, and HDL levels (Fu et al., 2015). Unlike Koren’s obesity. The first of which identified a decrease in diversity of team, Fu and colleagues did not find any variability in the gut gut microbiota in obese individuals, whereas this diversity was microbiota composition to be associated with elevated levels of increased with dietary weight loss (Turnbaugh et al., 2009). low-density lipoproteins (LDL) or total cholesterol levels, which A meta-analysis found that studies tend to report shifts in are not included as diagnostic criteria for metabolic syndrome different microbes associated with obesity (Walters et al., 2014). (Fu et al., 2015). Fu’s team identified 34 bacterial taxa that were This may be related to the functional redundancy in the gut associated with obesity, triglyceride and HDL levels in their microbiota, since multiple different taxa can contribute to the study group. Further, they determined that the gut microbiota same metabolic pathway. Walters and colleagues also noted composition accounted for nearly 26% of the variance observed that some of the variability of results reported between studies in HDL levels. These data suggest that treatments aimed at was due to differences in laboratory protocols and analytic altering the gut microbiota to increase levels of HDL cholesterol pipelines. For example, in the Turnbaugh and colleagues twin may have potential to be highly effective (Fu et al., 2015). study (Turnbaugh et al., 2009), a de novo approach was used which assigns operational taxonomic units (OTUs) without an Gut Microbiota and Blood Sugar external reference. In the meta-analysis assessing results of Obesity and adiposity are directly related to increased risk obesity associated microbiome changes using a closed-reference for elevated blood glucose levels and type 2 diabetes (Alberti OTU assignment process, where sequences that do not match et al., 2009). All diagnostic guidelines contain metrics for a reference data set are excluded; there were no significant impaired fasting glucose or impaired glucose tolerance, with or differences in the microbiota between obese and lean individuals without diabetes (Kaur, 2014). Some guidelines for metabolic (Turnbaugh et al., 2009). In addition to some of equivocal results syndrome use glucose metrics interchangeably with insulin observed when different laboratory and data processing pipelines resistance metrics (Kaur, 2014). Differences in gut microbiota are used, there is the question of the reproducibility of murine have been reported in individuals with type 2 diabetes, with studies in humans because there are significant differences in elevated levels of Bacteroidetes and Proteobacteria and lower how the different species maintain energy homeostasis as diet and levels of Firmicutes than healthy individuals (Larsen et al., metabolic demands are different (Turnbaugh et al., 2009). There 2010). Interestingly, in Larsen’s study, they did not observe are few studies evaluating processes identified as contributing the commonly reported decreased level of Bacteroidetes in to obesity in murine models and in human populations, the individuals that were diabetics and also obese. However, others same applies to most of the components of metabolic syndrome have observed that the composition of the gut microbiota in (Rosenbaum et al., 2015). Studies are increasingly evaluating obese individuals with insulin resistance or elevated glucose host genetic signatures as well as the microbiota to address levels agree with previous studies reporting lower levels of these issues. Studies designed in this manner have identified Bacteroidetes and butyrate producing species (Qin et al., 2012; features in the gut microbiome that suggest a strong relationship Vrieze et al., 2012). As discussed previously, obesity can between certain microbes and host genomic loci that are linked contribute to the development of this phenotype by increasing to obesity in human populations (Le Chatelier et al., 2013). insulin resistance, resulting in higher levels of glucose remaining Despite this ambiguity, continuing studies of the human gut in the serum. A small intervention study (N = 18, n = microbiota aim to refine result of the work that has been done 9/group) reported an increase in bacterial diversity in the gut thus far. when microbiota from lean donors was transplanted into obese recipients; with an associated increase in butyrate producing Gut Microbiota and Dyslipidemia bacteria and subsequent increase in insulin sensitivity (Vrieze All diagnostic guidelines for metabolic syndrome include metrics et al., 2012). of dyslipidemia, particularly high levels of triglycerides and A. muciniphila levels were found to be inversely associated to low levels of high-density lipoprotein (HDL) (Kaur, 2014). All obesity and diabetes in several animal and human studies (Tilg consistently categorize triglycerides as elevated when serum and Moschen, 2014). The role of A. muciniphila in reducing levels are above 150 mg/dL, and there is some variability inflammation could provide protection against the development between guidelines about what constitutes low HDL levels among of type 2 diabetes (Schneeberger et al., 2015). In addition, men and women (Kaur, 2014). Some bacterial taxa from the administration of A. muciniphila reduced body weight, adipose human gut are present in artherosclerotic plaques, although tissue inflammation, lipidemia, and hyperglycemia in diabetic the community of microbes within the plaque most closely and obese animals and increased adipose tissue browning and resembles bacterial taxa that predominate in the oral cavity fatty acid oxidation (Tilg and Moschen, 2014). However, two (Koren et al., 2011). Two uncharacterized taxa in the human recent studies reported increased levels of A. muciniphila in gut, from the Erysipelotrichaceae and Lachnospiraceae families, animals fed with high fat and high carbohydrate diet (Carmody were correlated with total cholesterol and LDL levels, but no et al., 2015; Hamilton et al., 2015). In human studies, it was association was observed related to serum HDL levels (Koren found that under certain levels of A. muciniphila, human subjects et al., 2011). A recent study evaluating the relationship between responded less efficiently to caloric restriction diet in terms of the human gut microbiota and blood lipid levels found that the reduction of hypergycemia, insulin resistance and inflammatory gut microbiota has significant differences in the same metrics that markers (Hamilton et al., 2015). However, there is no simple are characteristics of metabolic syndrome, namely obesity, serum relationship between levels of A. municiphila and inflammation,

Frontiers in Pharmacology | www.frontiersin.org 13 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients and the threshold beyond which a shift occurs between healthy to from diet (Scalbert et al., 2005). Their chemical structures are pathological conditions is still unknown (Hamilton et al., 2015). characterized by the presence of polyhydroxyphenyl units and Together, these studies suggest that the composition/diversity range from simple monomers and oligomers to highly polymeric of gut microbiota may contribute to elevated glucose levels and compounds with molecular weight reaching up to 30,000 Da, insulin resistance in individuals with metabolic syndrome. such as condensed tannins (Tsao, 2010). Polyphenols can be further classified according to their chemical structures into two Gut Microbiota and Metabolic Syndrome subgroups: flavonoids and non-flavonoid polyphenols, including Many of the studies evaluating the gut microbiota related to phenolic acids. They predominantly exist in combination with the risk factors associated with metabolic syndrome report sugars or acylated sugars (glycosides), but may also occur in other associations among multiple features of metabolic syndrome conjugated structures (amides, esters, and methyl ethers) or in (Rial et al., 2016). Given that multiple risks occur concurrently, their free forms (Tsao, 2010). even in the absence of metabolic syndrome (i.e., having only Flavonoids form the largest group of polyphenolic compounds 2 of the associated risk factors), it is difficult to disentangle with more than 6000 compounds identified and/or isolated from the individual contribution to disease state without considering plant sources (Kumar and Pandey, 2013). For a polyphenol to confounding factors. Some of the associations with multiple risk be classified as a flavonoid, its structure has to contain a benzo- factors suggest that the gut microbiome is intimately involved pyrane (chromane) moiety included in a C6-C3-C6 structural with observed variations over and above those related to age, sex, backbone (Figure 2), in which the two C6 units are benzyl rings and host genetics (Rial et al., 2016). Notably 12 bacterial OTUs (ring A and ring B) and C3 unit is the chromane ring (ring C). have been associated with variability across three traits (BMI, Depending on the hydroxylation and substitution patterns, as triglycerides, and HDL levels) (Fu et al., 2015). Others have found well as the degree of saturation of the chromane ring, flavonoids that lower diversity associated with obesity is also associated with can be further divided into several classes such as: flavones, insulin resistance and dyslipidemia (Le Chatelier et al., 2013). flavonols, flavanones, flavanonol, flavan-3-ols, anthocyanins, Because of confounding of characteristics associated with and isoflavones (Figure 3). Condensed tannins, also known as obesity, dyslipidemia, and elevated blood glucose levels, some proanthocyanidins or polyflavonoid tannins, are polymers of scientists have evaluated the human gut microbiota composition flavan-3-ols or flavan-3,4-diols (Figure 3). In all flavonoid classes, specifically related to metabolic syndrome. Similar to what is the ring B is attached to the carbon-2 of ring C; with the exception observed in obese individuals by Turnbaugh’s group (Turnbaugh of isoflavonoids in which the attachment between the two rings et al., 2009), a lower level of diversity of gut microbes was takes places at carbon-3 of ring C. Interestingly, this particular present in individuals with metabolic syndrome; and some arrangement has conferred isoflavones the ability to interact with of the taxa associated with metabolic syndrome are linked estrogen receptor and to act as weak phytoestrogens (Ozdal et al., to a genetic variant in the apolipoprotein A5 gene (APOA5) 2016). (Lim et al., 2016). Specifically, Lim and colleagues noted that The nonflavonoid-polyphenols have more heterogeneous specific taxa associated with metabolic syndrome were not all structures and broadly comprises hydrolysable tannins correlated with each characteristic of metabolic syndrome in (gallotannins and elagitannins), lignans stilbenes, and phenolic the same way. For example, they found Lactobacillus to be acids). Phenolic acids in food are mainly benzoic acid or correlated with central obesity and fasting blood sugar, but cinnamic acid derivatives (Lafay and Gil-Izquierdo, 2008). negatively correlated with HDL levels (Lim et al., 2016). This Some phenolic acids such as p-coumaric and hydroxyl-cinnamic suggests that metabolites from gut metabolism contribute to multiple mechanistic pathways involved in metabolic syndrome and that there may be different combinations of contributing microbes depending on which characteristics of metabolic syndrome are present in an individual (Lim et al., 2016). This suggests that multiple interventions may be effective for treating and preventing metabolic syndrome by targeting mechanistic pathways associated with different characteristics of metabolic syndrome.

THERAPEUTIC MODULATION OF GUT MICROBIOTA TO RESTORE LIPID AND GLUCOSE HOMEOSTASIS Polyphenols Polyphenols constitute a large group of heterogeneous secondary metabolites found almost ubiquitously in the plant kingdom. The daily intake of dietary phenols is estimated to be larger FIGURE 2 | The basic structure of flavonoids. than 1 g, which is 10 times higher than vitamin C intake

Frontiers in Pharmacology | www.frontiersin.org 14 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

FIGURE 3 | Chemical structures of main classes of flavonoids showing positions of potential C-ring cleavage (——) or A-ring cleavage (——). acids are considered “functional polyphenols” despite their Over the last few decades, research on polyphenols has monophenolic structures because they share many properties expanded exponentially and many other biological activities with polyphenols (Pereira et al., 2009). and health benefits have been attributed to polyphenols. These Polyphenols are produced in plants to serve important roles include, but are not limited to, anti-inflammatory, anticancer, such as protection against different environmental stressors and protective activities against inflammatory and oxidative and pathological aggressions, thus acting as primary defense stress-induced disorders such as aging, rheumatoid arthritis, mechanisms (phytoalexins). For this reason, polyphenols are diabetes mellitus, cardiovascular and neurodegenerative diseases endowed with excellent antioxidant, antifungal, antibacterial, and (Li et al., 2014). As data accumulated from research studying the photo-protective properties (Li et al., 2014). mode of actions of polyphenols, it soon became clear that their

Frontiers in Pharmacology | www.frontiersin.org 15 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients health benefits go beyond antioxidant potential (Scalbert et al., tea catechins, quercetin and citrus flavonoids attenuated hepatic 2005). gluconeogensis in diabetic mice and rats through the inhibition Scientific interest in polyphenols has rapidly grown in the of the key gluconeogenic enzymes glucose-6-phosphatase and late twentieth century following many epidemiological studies phosphoenolpyruvate carboxykinase (Bahadoran et al., 2013; linking the consumption of polyphenol-rich food such as Eid and Haddad, 2017). Hepatic glucose kinase and glycogen fruits and vegetables to lower risk of developing cancer and synthase can also be modulated by polyphenols such as ferulic cardiovascular diseases (Pandey and Rizvi, 2009). Of note, the and hydroxylcinnamic acid derivatives (Bahadoran et al., 2013). hypothesis that polyphenols constitute the active ingredients in The molecular mechanisms of polyphenols’ antidiabetic food was supported by a wealth of in vitro and animal studies actions also include stimulation of insulin production and using isolated pure phenolic compounds (Gao and Hu, 2010). protection of pancreatic β cell against hyperglycemia-induced However, bioavailability studies in animal and human subjects oxidative stress and promotion of β cell proliferation and survival have shown poor absorption and extensive hepatic metabolism of in both in vitro and in vivo studies (Vinayagam and Xu, 2015). phenolic compounds, thus raising concerns on the applicability Because of their unique chemical structures, polyphenols are of in vitro studies in which parent phenolic compounds were used powerful antioxidants. Green tea had the ability to scavenge (Gao and Hu, 2010). In addition, these compounds were tested 100% of superoxide anion and 86% of other reactive oxygen at concentrations (in µM) much higher than those achieved species (ROS) (Umeno et al., 2016). The radical scavenging in vivo (in nM) (Gao and Hu, 2010). Thus, the following properties of polyphenols were studied in vitro and were question arises: why are polyphenols bioactive despite low plasma attributed to either modulation of enzymes responsible for concentrations? In order to answer this question, it should the production of ROS including cyclooxygenase, lipoxygenase, be taken into account that the dietary intake of polyphenols xanthine oxidase, microsomal monooxygenase, and NADH is estimated to reach values up to g quantities/day which is oxidase (Bahadoran et al., 2013) or to the enhancement equivalent to mM levels of polyphenols and their metabolites in of the endogenous antioxidative defense system through the the gut (Grosso et al., 2017). It has thus been proposed that gut modulation of antioxidant enzymes like superoxide dismutase, microbiota play a crucial rule in polyphenols’ metabolism and catalase, and glutathione reducatse (Bahadoran et al., 2013). activities (Williamson, 2013). However, it is not clear if these in vitro results could be This section focuses on polyphenols-microbiota reciprocal reproduced in vivo (Halliwell et al., 2005). In addition, when interactions and their pivotal role in attenuating metabolic biomarkers of the antioxidant activities of polyphenols in syndrome and type 2 diabetes mellitus. animal and human subjects, including decreased LDL and DNA oxidation and increased plasma total antioxidant potential, were Polyphenols as Antidiabetic and Anti-Obesity Agents evaluated using fruit juices, soy or vegetables, it was found The antidibetic potential of polyphenols has been extensively that the observed beneficial effect might not be attributed to studied and documented. In vitro studies show that polyphenols polyphenols (Halliwell et al., 2005). The same authors proposed can inhibit the enzymes of dietary carbohydrate and lipid that the antioxidant activities of polyphenols could actually occur digestion such as α-glucosidase, α-amylase, and pancreatic lipase in the GI tract before absorption. They argued that, at best, therefore reducing glucose and fatty acid intestinal absorption polyphenol plasma concentrations do not exceed 1 µM, which (Hanhineva et al., 2010). Several polyphenols such as quercetin, are much lower than the concentrations they can reach in the tea catechins, chlorogenic caffeic, and gallic acids were also gut, whereby the microbial fermentation products of polyphenols reported to inhibit glucose absorption in intestinal Caco2 cell line could be responsible for a greater proportion of antioxidant as well as brush-border-membrane vesicles of porcine jejunum activities (Halliwell et al., 2005). via the inhibition of sodium-dependent SGLT1 transporters In addition to their antidiabetic properties, the antiobesity (Hanhineva et al., 2010). GLUT2 was similarly inhibited by potential of some polyphenols is well documented in cell several flavonoids including quercetin, myricetin, neohesperidin, culture, animal and clinical studies (Wang et al., 2014). and catechin (Johnston et al., 2005; Kwon et al., 2007). Resveratrol as well as green tea extract and its catechins, The insulin-responsive GLUT4, another glucose transporter particularly epigallocatechin gallate (EGCG), were reported to responsible for glucose uptake in insulin-sensitive tissues, suppress adipocyte differentiation in 3T3-L1 cell line through seems to be the target of many polyphenols. Some polyphenols the activation of AMPK and the down regulation of adipogenic stimulated GLUT4 translocation in adipocytes or skeletal factors including peroxisome proliferator activator receptor γ muscle cells by activating either the insulin-mediated (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) phosphatidylinositide 3-kinase (PI3-K)/Akt or the AMP- (Wang et al., 2014). Animal studies supported the effects of activated protein kinase (AMPK) pathways (Eid et al., 2015; the aforementioned flavonoids on obesity-related inflammation Hajiaghaalipour et al., 2015). Regulation of AMPK activity can and other obesity parameters such as body weight, total lipids, also leads to the activation of a class of protein deacetylases cholesterol and triglyceride (Khurana et al., 2013). In addition, known as sirtuins. Activation of sirtuin 1 (Sirt1) is involved in enhanced fat oxidation in adipose tissue and skeletal muscle was the antiaging and anti-inflammatory effects of polyphenols such reported in two obesity models: diet-induced obesity and ob/ob as resveratrol, querectin, catechins, and piceatannol (Chung mice models treated with flavonoids (Khurana et al., 2013). et al., 2010). Polyphenols may also enhance glucose homeostasis Clinical and epidemiological studies further confirmed the by modulating hepatic glucose metabolism. Flavonoids such as beneficial effects of certain polyphenols. A meta-analysis of

Frontiers in Pharmacology | www.frontiersin.org 16 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

24 randomized clinical trials (RCTs) has documented the together with the conjugates secreted in bile, deconjugation, improvement of insulin resistance after daily consumption of and degradation by microbial enzymes to smaller phenolic flavonoid-rich cocoa beverages (Shrime et al., 2011; Ellinger compounds before being absorbed (Stevens and Maier, 2016). and Stehle, 2016). Similarly, ingestion of chocolate, cacao Oligomeric flavonoids are first degraded in the stomach to or flavan-3-ol has significantly reduced insulin resistance monomers and dimers while larger polymeric compounds such and major cardiovascular diseases risk (CVD) factors in as ellagitannins are taken to the colon to be degraded by resident another meta-analysis of 42 RCTs (Hooper et al., 2008). bacteria to their monomers (Kumar and Pandey, 2013). Nevertheless, some other RCTs reported inconsistent results. For Phenolic acids existing in free form, or conjugated to sugars, example, consumption of green tea containing 456 mg catechins quinic, or shikimic acids, are absorbed from the small intestine (Fukino et al., 2005) or isoflavonoids in a 6-month RCT in after the hydrolysis of the conjugated forms. Importantly, the postmenopausal Chinese women (Liu et al., 2010) did not most abundant phenolic acids caffeic acid and ferulic acids are prove beneficial regarding glucose levels or insulin resistance found generally bound to cell wall components such as lignins markers. Epidemiological studies also yielded conflicting results. and polysaccharides and are therefore subject to colon microbial A meta-analysis of 6 prospective cohort studies involving metabolism (Russell et al., 2009). 284.806 participants has reported a significant inverse association Gut microbes are not only capable of cleaving polyphenols between total polyphenols consumption and risk for type 2 glycosides and glucuronides, but they can also cleave the carbon- diabetes in the US population (Liu et al., 2014). However, carbon bonds of heterocyclic and aromatic rings as well as some inconsistent effects were found in other subgroups (Liu decarboxylate, dehydoxylate, and hydrogenate alkene side chains et al., 2014). Similar negative results were reported from other (Stevens and Maier, 2016). The site of C-C cleavage seems to cross-sectional studies attempting to relate protection against depend on the flavonoid subclass: in anthocyanidins, flavonols, diabetes to the intake of total flavonols and flavones (Song flavones, and flavanones, the cleavage occurs in ring-C, while in et al., 2005) or anthocyanins in the Iowa women (Nettleton flavanols, it also takes place in ring-A (Figure 3). et al., 2006). Inconsistent findings were also reported from RCTs Phenolic acids are the major metabolites of flavonoids investigating the antiobesity effects of flavonoids such as EGCG, detected in circulation and urine (Stevens and Maier, resveratrol, and curcumin (Wang et al., 2014). Several factors 2016). Ring-C cleavage of anthocyanins produces many might account for such inconclusive antidiabetic and anti-obesity phenolic acids such protocatechuic (PCA), gallic, 3-O- clinical outcomes. Those include the duration of the study, methyl-gallic, syringic, p-coumaric, and vanillic acids, as age, gender, and ethnicity of participants or the varieties of well as 2,4,6-trihydroxybenzaldehyde (Duda-Chodak et al., polyphenols present in the diet. 2015). Interestingly, many biological activities have been attributed to PCA such as antioxidant, anti-inflammatory, Metabolism of Polyphenols by Gut Microbiota antihyperglycemic, antiatherogenic, hypocholeserolemic, Initial bioavailability studies have reported poor absorption of anticancer, and neuroprotective actions (Duda-Chodak et al., flavonoids from food sources (Thilakarathna and Rupasinghe, 2015). In addition, anthocyanin metabolites, namely gallic 2013). Polyphenols are rarely found in nature in the free form. acid, 3-O-methyl-gallic acid, and 2,4,6-trihydroxybenzaldehyde, The majority of flavonoids monomer, except catechins, exist as were more effective as cytotoxic compounds than the parent β-glycosides (Marin et al., 2015). Catechins, being in the free anthocyanin (Forester and Waterhouse, 2010). Similarly, form, are rapidly absorbed from the small intestine. On the other flavonols such as quercetin are metabolized to PCA and 2-(2,4,6- hand, the sugar moiety of the flavonoid glycosides determines trihyrdoxyphenyl)-acetic acid, which can be further converted their site of absorption. Hollman et al. (1995) detected the to their o-methyl conjugates. Flavanols such as catechin, presence of quercetin glucoside in the circulation after ingestion epicatechin, and ECGC undergo both A-ring and C-ring cleavage of onion powder. Transport through SGLT1 was suggested as to form 3-hydroxyphenylacetic acid, 3-hydroxyphenylpropionic the mechanism of absorption (Hollman et al., 1995). Other acid, 3,4-dihydroxyphenylacetic acid, and 3-hydroxyphenyl- studies suggested that glucosides could also be hydrolyzed by γ-valerolactone. Demethylation and ring-C fission of the lactase phlorizin hydrolase (LPH), a β-glucosidase present in the isoflavonoid diadezein generates the major metabolite O- intestinal brush border microvilli, to release the free aglycone. demethyl-langlensin (Stevens and Maier, 2016). Ellagitannins Absorbed agylcones mainly undergo hepatic phase II metabolism are degraded to ellagic acid, which is further metabolized by the to form methyl, sulfate, and glucuronide conjugates (Marin colon microflora to the phenolic metabolites called urolithins. et al., 2015). Other glycosides such as rhamnosides, arabinosides, Phenolic acids such as caffeic acid and its ester chlorogenic and galactosides as well as some glucosides including cyanidin- acid are metabolized by the microflora to phenylpropionic, 3-glucoisde and the isoflavonoid daidzein-7-glucoside are not benzoic and, hippuric acids (Gonthier et al., 2003). Caffeic acid efficiently hydrolyzed by this enzyme and are moved to the colon can also undergo decarboxylation and transformation by gut where they are hydrolyzed and degraded by the colon microbiota microbiota into 4-ethyl catechol (Ozdal et al., 2016). Lignans (Marin et al., 2015). such as pinoresinol and syringaresinol are biotransformed to Studies have reported that only 5–10% of dietary polyphenols enterolactone and enterodiol, two phtoestrogens responsible can be absorbed from the small intestine. The remaining for estrogenic agonistic/antagonistic activities of lignans (Ozdal non absorbed (90–95%) polyphenols reach the colon at high et al., 2016). Finally, microbial communities also possess concentrations (up to the mM range) where they undergo, glucuronidases and sulphatases, thus transforming phase II

Frontiers in Pharmacology | www.frontiersin.org 17 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients metabolites into the free form and enabling their absorption into Interestingly, incubation of anthocyanins with fecal bacteria in the general circulation (Cardona et al., 2013). stirred, batch-culture fermentation vessels simulating human The biological activities of the microbial metabolites of colon conditions resulted in an increase of the beneficial polyphenols are still under investigation. However, because they Bifidobacterium spp. and Lactobacillus-Enterococcus spp. levels are efficiently absorbed by the GI tract, they are believed to be (Hidalgo et al., 2012). responsible for the health promoting activities of polyphenols More interesting results have emerged from in vivo and (Cardona et al., 2013). In a recent study, the two metabolites clinical studies. Ellagitannin-rich pomegranate extract (POME) 3-hydroxyhippuric acid and 3-hydroxyphenyl acetic acid were and ellagitannins main metabolite urolithin-A were reported found to reach and accumulate in the brain of rats treated with to significantly enhance the growth of Bifidobacterium and grape seed phenol extract in a dose dependent manner (Wang D. Lactobacillus spp. in a rat model of colitis. Interestingly, et al., 2015). urolithin-A has shown more powerful anti-inflammatory properties than the parent ellagitannin-rich extract (Larrosa Modulation of Microbiota by Polyphenols et al., 2010). In a clinical study, the consumption of 1,000 mg of Because of their distinctive structures, polyphenols have shown a POME by 20 healthy volunteers for 4 weeks resulted in beneficial great potential as antimicrobial agents against human pathogens changes in the gut microbiota of participants who were able to in experimental and clinical studies (Coppo and Marchese, 2014). metabolize ellagitannins to urolithin-A. These changes include Their activities against gastrointestinal tract pathogens (Selma reduction in Firmicutes levels and the induction of the growth et al., 2009) are of particular interest to this review. Commensal of Enterobacter, Lactobacillus, E. coli, and Verrucomicrobia and probiotic microorganisms such as strains of Lactobacillus, (A. muciphila). The latter two bacterial strains were reported Streptoccoccus, Bifidobacteria, and the yeast Saccharomyces to preserve the intestinal mucus and the glycocalyx layer and boulardii are known to preserve epithelial integrity, protect to reduce the intestinal permeability frequently associated with against enteric pathogen, and serve other important function development of inflammation and metabolic diseases (Zhang such as modulating sugar and lipid metabolism. The gut can and Zhang, 2013). also be inhabited by pathogenic bacteria that cause GI illness Of note, administration of both quercetin and resveratrol such as inflammatory bowel disease caused by Clostridium (Etxeberria et al., 2015), or resveratrol alone (Qiao et al., 2014), difficile infection (Bien et al., 2013). Dysbiosis is the term that to obese rat fed high fat/high sucrose (HFHS) or high fat diets describes the imbalance between the beneficial and pathogenic was reported to reduce F/B ratio (Qiao et al., 2014; Etxeberria bacteria. It has been associated with many chronic diseases et al., 2015). Moreover, it decreased the abundance of bacteria including metabolic disorders such as obesity and type 2 associated with diet-induced obesity, such as Bacillus spp., diabetes (Carding et al., 2015). Since Firmicutes possess fewer Eubacterium cylindroide, and Erysipelotrichaceae (Etxeberria enzymes than Bacteriodetes capable of degrading glycans, et al., 2015) and increased the growth of Bifidobacterium and products of polyphenol glycoside hydrolysis, it was suggested Lactobacillus (Qiao et al., 2014; Etxeberria et al., 2015). that the intake of polyphenols could influence the composition The highly polymeric apple procyanidins administered for 20 of gut microbiota in favor of beneficial bacteria with health weeks to C57BL/6J mice fed a HFHS diet attenuated weight gain promoting functions (Cardona et al., 2013). Thus, it is deemed and caused a reduction in inflammation and gut permeability, necessary to investigate the effect of polyphenols on human gut as well as modulation of lipid metabolizing genes (Masumoto bacterial growth. et al., 2016). Similarly, apple peal polyphenols upregulated The modulation of gut microbiota by polyphenols was antioxidant enzymes and attenuated experimental inflammatory firstly studied in vitro. One study examined the effect of some bowel disease (Denis et al., 2016). Furthermore, F/B proportion flavonoids aglycones and their glycosides on representative was markedly decreased and Akkermansia levels were increased species of human gut microbial communities (Bacteroides eight-fold by the end of the treatment (Masumoto et al., 2016). galacturonicus, Lactobacillus sp., Enterococcus coccae, Grape/red wine polyphenols (Roopchand et al., 2015) and Bifidobacterium catenulatum, Ruminococcus gauvreauii, E. coli). procyanidin-rich cranberry extract (Anhe et al., 2015a) showed The aglycones quercetin, naringenin and hesperetin but not similar effects on obesity, metabolic syndrome parameters and their glycosides rutin, naringin and hesperidin inhibited the levels of Akkermansia in mice fed a high-fat diet (Anhe et al., growth of certain tested bacteria (Duda-Chodak et al., 2015). In 2015a; Roopchand et al., 2015). the same study, catechin had no impact on the growth of the Collectively, these studies reveal that polyphenols act aforementioned bacteria (Duda-Chodak et al., 2015). In another as prebiotic supplements that can positively modulate gut in vitro study, the flavonol galangin but not quercetin or fisetin microbiota composition mainly through the enrichment of inhibited the growth of B. adolescens (Kawabata et al., 2013). beneficial bacteria and the inhibition of pathogenic bacterial Similarly, the effects of the common dietary polyphenols on the growth (Anhe et al., 2015b; Le Barz et al., 2015; Fändriks, 2017). growth and adhesion of commensal and pathogenic bacteria to enterocytes were studied in the Caco2 cell line (Parkar et al., Polysaccharides 2008). At their physiological concentration, all polyphenols, Carbohydrates are classified based on the number of linked except rutin, affected the viability of representative gut flora. carbohydrate units into mono-, oligo-, and poly-saccharides However, one of the major limitations of in vitro studies is (Cummings and Stephen, 2007). For instance, glucose, fructose, that 80% of the bacteria in the human gut are uncultured. and galactose are monosaccharides whereas lactose, sucrose, and

Frontiers in Pharmacology | www.frontiersin.org 18 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients maltose are disaccharides. Common oligosaccharides include rectale, Eubacterium hallii, and Ruminococcus bromii, produce fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), butyrate (Louis et al., 2010). Propionates and butyrates lower and mannan oligosaccharides (MOS). Arabinoxylans, cellulose, lipogenesis and serum cholesterol level while activating intestinal chitin, and pectins are examples of polysaccharides having linear gluconeogenesis (IGN) which contributes to glucose homeostasis or branched structures (Cummings and Stephen, 2007). (Hosseini et al., 2011). Another classification is based on whether carbohydrates SCFA are ligands of the free fatty acid receptor (FFAR) are digestible and non-digestible. Starch, dextrin, glycogen are 2 and 3, also known as G-protein coupled receptor (GPR) some of the digestible polysaccharides, while non-digestible 43 and 41, respectively. FFAR2 is activated by acetate and carbohydrates (NDCs) (Paeschke and Aimutis, 2010) are listed propionate, while FFAR3 is activated by propionate and butyrate in Table 7 (Kaushik et al., 1989). (Kaji et al., 2014). Propionate is involved in gluconeogenic activity while acetate and butyrate contribute to lipogenic activity Gut Microbiota and Dietary Intake (den Besten et al., 2013a). These three gut bacterial products Some of the gut’s microbial species are infulenced by the (acetate, propionate, and butyrate) thus regulate gluconeogenesis composition of the diet (Kok et al., 1996; Wu et al., 2011; and lipogenesis, thereby modulating hepatic lipid and glucose Pyra et al., 2012). Firmicutes and Proteobacteria (Prevotella homeostasis, notably through PPAR-γ (den Besten et al., 2015). enterotype) thrive under diets that are rich in carbohydrates and SCFAs produced from dietary fibers can also increase LPS (Blaut simple sugars (such as glucose and fructose), while Bacteroidetes and Klaus, 2012), the main component of gram-negative bacteria and Actinobacteria (Bacteroides enterotype) are favored by diets (Delzenne and Cani, 2011). Plasma LPS participates in the rich in saturated fat and animal protein. Fat and protein decrease development of insulin resistance, as discussed by Carvalho et al. the microbial diversity of the intestine, whereas carbohydrates (2012). In contrast to SCFAs, high concentrations of omega-3 increase it (Wu et al., 2011). Oligo- and poly-saccharides enhance fatty acids reduce LPS (Kaliannan et al., 2015), as do Gram- the concentration of the species belonging to Actinobacteria positive bacteria (Bifidobacterium and Lactobacillus) (Zhang and Firmicutes phyla except for Staphylococcus (Staphylococcus et al., 2010). aureus), Clostridium (C. difficile, Clostridium leptum, Clostridium On the other hand, the activity of gut microbiota influences perfringens). Proteobacteria phyla show the opposite trend, triglycerides, which represent stored glycerol-linked fatty acids whereas Bacteroidetes and Verrucomicrobia show a mixed trend (den Besten et al., 2013b). Different concentrations of cholesterol, (Wu et al., 2011). lipoproteins, and triglycerides determine the classification Actions of Oligo- and Poly-saccharides of circulating lipids into chylomicrons, very low-density Oligo- and poly-saccharides exert a significant influence on lipoproteins (VLDL), intermediate-density lipoproteins (IDL), the gut microbiota. In general, oligo- and poly-saccharides low-density lipoproteins (LDL), and high-density lipoproteins increase short-chain fatty acids (SCFA), GLP-1, and PYY, while (HDL) (Cox and Garcia-Palmieri, 1990). It is well-established decreasing triglycerides, VLDL, and LDL, with a mixed trend that diets rich in fructose can increase triglycerides (Schaefer being observed for HDL (Morrison and Preston, 2016), as shown et al., 2009). High triglyceride levels, in turn, bring out in Table 8. These changes and their metabolic consequences will undesirable effects on lipid metabolism (Reiser, 1985) and, be summarized below. as detailed above, are one of the hallmarks of the metabolic Firstly, the fermentation of non-digestible carbohydrates syndrome. In contrast, decreased triglyceride levels reduce takes place in the gut and produces SCFAs, with acetate, fatty acid synthase activity (Morand et al., 1994) and provide propionate, and butyrate (Morrison and Preston, 2016) present beneficial health effects. Several polysaccharides such as inulin, in a ratio of 3:1:1 (Hoverstad et al., 1984). More specifically, A. FOS, GOS, OFS, ITF, fructans, β-glucans, arabinoxylans, xylo- municiphilla produce propionates (Derrien et al., 2004) while oligosaccharides, polydextrose, resistant starch, and guar gum Ruminococcus bromii (Ze et al., 2012) F. prausnitzii, Eubacterium decrease triglyceride levels (de Deckere et al., 1993).

TABLE 7 | Examples of NDCs.

Class Example

Fructans Inulin, FOS, oligofructose (OFS), levan Galactans (Galactooligosaccharides) GOS, trans-galactooligosaccharides (TOS) Grains, fruits, vegetables-oligo and polysaccharides Pectin, β-glucan, cellulose, hemicellulose, arabinoxylan, arabinoxylooligosaccharides (AXOS) Synthetic NDCs Polydextrose, resistant maltodextrin Resistant starches (Type 1 to 4) Galactomannan polysaccharides Gums of guar, hydrolyzed guar, locust bean, genugreek, tara Microbial polysaccharides Xanthan and gellan gum Seaweed polysaccharides Alginate Glucomannan polysaccharides Konjac Tree exudate polysaccharides Gum arabic, gum acacia, karaya, tragacanth and ghatti gums

Frontiers in Pharmacology | www.frontiersin.org 19 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients Liu F. et al., ) ecreases ( Bindels ecreases ( Hashmi ecreases ( 016 ) t al., 2016 ) t al., 2012; LDL e D e D 2 D Rendon-Huerta et al., 2012; Chan et al., 2016 Parnell and Neyrinck creases ( Hong et al., creases ( Delzenne creases ( creases ( eimer, 2009 ) 016 ) t al., 2005 ) t al., 2012 ) R e PYY In 2 In e In In Kok et al., ) creases ( Kok et al., creases creases ( Hong et al., ecreases ( 996; Pyra et al., 2012; 005 ) 012 ) 996; Rajpal et al., 1 Hashmi et al., 2016 ) ( Rendon-Huerta et al., 2 2 HDL In D In In 1 2015; Liu F. et al., 2016 ) ) Hira et al., 2015 ) Malaguarnera Olli et al., 2015 ) ) creases ( Delzenne et al., creases ( Delzenne et al., creases ( Parnell and creases ( creases ( Keenan et al., creases ( Williams, 1999; creases ( Hong et al., eimer, 2009 ) dam and 003; Hong et al., 2016 ) 016 ) 005 ) 007; Koleva et al., 2012; 015 ) t al., 2012; Neyrinck et al., In In 2 2 R Increases ( 2 A GLP-1 Increases ( Piche et al., 2 2 In Mao et al., 2015; Liuet T. W. al., 2016 In In e 2012; Salazar et al., 2015; Liu F. et al., 2016 Increases ( In In Westerterp-Plantenga, 2005 Delzenne et al., ) ecreases ( ecreases ( Hashmi et al., ecreases ( Delzenne et al., 002; Koleva et al., 2012; 016 ) 002; Russo et al., 2008 ) VLDL D 2 Mao et al., 2015; Hashmi et al., 2016; Liu T. W.2016 et al., D 2 D 2 Daubioul et al., Backhed et al., Hong et al., den Besten Russo et al., Modler, 1994; ) su et al., 2004; Salazar ecreases ( Marquez-Aguirre ecreases ( Adam et al., ecreases ( ecreases ( Modler, 1994 ) ecreases ( Hashmi et al., 008 016 ) 002 ) 004 ) 005; Riviere et al., 2016 ) 001 ) t al., 2016 ) t al., 2013 ) t al., 2014 ) TG Decreases ( 2 Decreases ( 2 D e Decreases ( 2 2 et al., 2015 ) Decreases ( e D 2 D D 2 D Decreases [68] e Decreases ( H ) ) Van den Abbeele Woods and Woods and Clarke et al., Backhed et al., Hu et al., 2016 ) Decreases ( Bronkowska orbach, 2001 orbach, 2001 ) orbach, 2001 ) 016 ) 004; Delzenne et al., 2007; t al., 2011 ) G e SCFA G G 2 2 Wu et al., 2010; Geraylou et al., 2013 Influence of oligo- and poly-saccharides on key metabolic regulators. glucans F FS uar gum OS Increases ( MD S Increases ( Xs Increases ( XOS Increases ( DX OS ructans Increases ( OS Increases ( TABLE 8 | Inulin Increases ( Woods and A F G R G P O IT F A X R β -

Frontiers in Pharmacology | www.frontiersin.org 20 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Dietary carbohydrates also modulate important incretin and Lactobacillus species with central obesity and fasting hormones, namely glucose-dependent insulinotropic peptide hyperglycemia. (GIP) and glucagon-like peptide-1 (GLP-1) (Edholm et al., 2010). Polyphenols, oligo-, and poly-saccharides can influence the Endocrine K-cells secrete GIP in response to carbohydrates composition of gut microbiota by favoring beneficial bacteria and and fat ingestion, (Andersen et al., 1978) whereas, GLP- inhibiting growth and activity of pathogenic species and thus 1 is secreted by L cells (Kieffer and Habener, 1999) in constitute a promising avenue for the prevention and treatment response to luminal sugars, amino acids and fatty acids of metabolic disorders. (Holst, 2007). GLP-1 stimulates the release of insulin, suppresses the release of glucagon (Nadkarni et al., 2014), FUTURE CHALLENGES AND lowers the blood glucose (Nauck et al., 1993), and plays a OPPORTUNITIES major role in glucose homeostasis (Kieffer and Habener, 1999; Deacon, 2004). GIP exerts similar effects (Yabe and Given all the above considerations, the perspectives for targeting Seino, 2011). Oligo- and poly-saccharides such as fructo- the gut microbiome in the context of metabolic diseases keeps oligosaccharides (FOS), Glucooligosaccharides (GOS), being highly relevant and timely. First and foremost, there oligofructoses (OFS), inulin-type fructans (ITF), fructans, remains a need to refine research on specific microbes that may Arabinoxylooligosaccharides (AXOS), resistant maltodextrin, be more specifically involved in metabolic diseases rather than resistant starch, and guar gum increase GLP-1 (Wang X. et al., considering broader categories, such as phyla. Among challenges 2015). that should be met, more studies should focus on the roles and Another important peptide hormone modulated by dietary potential mechanisms of action of non-bacterial gut microbes, carbohydrates is peptide YY (PYY), which is secreted by α-cells since these remain poorly understood. Continued research efforts of the pancreatic islets in response to the food that is ingested should also result in the better understanding of the modes of (Shi et al., 2015). External administration of SCFAs releases PYY action of pre- and pro-biotics in metabolic diseases, notably in and GLP-1 into plasma (Freeland and Wolever, 2010), while terms of metabolic and inflammatory mediators. generated SCFAs can increase PYY concentration only (Cherbut There also remains a lot to be done to further elucidate et al., 1998). When PYY concentration increases, serum insulin the intricate interactions between prebiotics (polyphenols and level also increases, which improves glucose tolerance (Shi et al., fibers) on the one hand, and probiotics (gut microbes), on the 2015) leading to GH regulation (Boey et al., 2007). Therefore, the other, notably in what pertains to the metabolism of prebiotics higher level of GLP-1, GIP, and PYY is desirable. by the latter and the influence this has on the bioactivity of Gut microbiota modulates the brown adipose tissues (BATs) the former. In this context, experimental approaches and tools (Mestdagh et al., 2012). When stimulated, FFA are used-up to have now evolved that can meet this challenge. For instance, clear the TGs (Bartelt et al., 2011) in turn regulating glucose one could think of combining bacterial metagenomics with plant homeostasis (Stanford et al., 2013)(Peirce and Vidal-Puig, 2013). metabolomics and hence study relationships through the use of Sodium-glucose transport protein-1 (SGLT-1) and glucose powerful bioinformatics. transporter-2 (GLUT-2) also participate in maintaining GH Overall, and in a very pragmatic sense, academics and (Kellett and Helliwell, 2000). industrial partners will need to work together to develop safe and reliable products that can help prevent and mitigate the ill SUMMARY effects of metabolic syndrome and related obesity and diabetes. In this context, a promising approach may be to further explore The healthy human gut represents a complex and highly variable symbiotic products that can combine pre- and pro-biotics in ecological system consisting of several microbes belonging to novel and efficient ways. bacteria, fungi and virus domains, in addition to host epithelial cells. Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, AUTHOR CONTRIBUTIONS and Fusobacteria are the major phyla colonizing the stomach and intestine of healthy adults. The exact role of gut microbiota HE, MW, NA, AQ, AA, and PH have written the first draft of the is not fully elucidated but many studies implicate microbiota to manuscript. SH, AM, SN, and LR revised and improved the first perform tasks that are known to be useful for the human host draft. All authors have seen and agreed on the final submitted such as modulating intermediate metabolism and the immune version of the manuscript. system. Diet-induced changes in the composition/diversity of gut microbes are thus believed to participate in the pathogenesis of ACKNOWLEDGMENTS certain diseases through modifying different metabolic processes in the host. AA acknowledges the support by the Polish KNOW (Leading Less diverse intestinal microbiota have been reported in National Research Centre) Scientific Consortium “Healthy metabolic disorders. While the association between increased Animal—Safe Food,” decision of Ministry of Science and Higher Firmicutes/Bacteroidetes ratio and metabolic diseases is still Education No. 05-1/KNOW2/2015, and by the Austrian Science controversial, more recent studies associated Akkermansia Fund (FWF): P25971–B23.

Frontiers in Pharmacology | www.frontiersin.org 21 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

REFERENCES Bien, J., Palagani, V., and Bozko, P. (2013). The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory Abeles, S. R., and Pride, D. T. (2014). Molecular bases and role of bowel disease? Therap. Adv. Gastroenterol. 6, 53–68. doi: 10.1177/1756283X12 viruses in the human microbiome. J. Mol. Biol. 426, 3892–3906. 454590 doi: 10.1016/j.jmb.2014.07.002 Bik, E. M., Eckburg, P. B., Gill, S. R., Nelson, K. E., Purdom, E. A., Francois, F., et al. Adam, A., Levrat-Verny, M. A., Lopez, H. W., Leuillet, M., Demigne, C., and (2006). Molecular analysis of the bacterial microbiota in the human stomach. Remesy, C. (2001). Whole wheat and triticale flours with differing viscosities Proc. Natl. Acad. Sci. U.S.A. 103, 732–737. doi: 10.1073/pnas.0506655103 stimulate cecal fermentations and lower plasma and hepatic lipids in rats. J. Bindels, L. B., Porporato, P., Dewulf, E. M., Verrax, J., Neyrinck, A. M., Nutr. 131, 1770–1776. Martin, J. C., et al. (2012). Gut microbiota-derived propionate reduces Adam, T. C., and Westerterp-Plantenga, M. S. (2005). Nutrient-stimulated GLP- cancer cell proliferation in the liver. Br. J. Cancer 107, 1337–1344. 1 release in normal-weight men and women. Horm. Metab. Res. 37, 111–117. doi: 10.1038/bjc.2012.409 doi: 10.1055/s-2005-861160 Blaut, M., and Klaus, S. (2012). Intestinal microbiota and obesity. Handb. Exp. Afsar, B., and Elsurer, R. (2014). The relationship between central hemodynamics, Pharmacol. 209, 251–273. doi: 10.1007/978-3-642-24716-3_11 morning blood pressure surge, glycemic control and sodium intake in patients Boey, D., Sainsbury, A., and Herzog, H. (2007). The role of peptide YY in regulating with type 2 diabetes and essential hypertension. Diabetes Res. Clin. Pract. 104, glucose homeostasis. Peptides 28, 390–395. doi: 10.1016/j.peptides.2006.07.031 420–426. doi: 10.1016/j.diabres.2014.03.011 Bratoeva, M. P., Wolf, M. K., Marks, J. K., and Cantey, J. R. (1994). A case of Alberti, K. G., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, diarrhea, bacteremia, and fever caused by a novel strain of Escherichia coli. J. K. A., et al. (2009). Harmonizing the metabolic syndrome. Circulation 120:1640. Clin. Microbiol. 32, 1383–1386. doi: 10.1161/CIRCULATIONAHA.109.192644 Bronkowska, M., Orzel, D., Lozna, K., Styczynska, M., Biernat, J., Gryszkin, A., Andersen, D. K., Elahi, D., Brown, J. C., Tobin, J. D., and Andres, R. (1978). Oral et al. (2013). Effect of resistant starch RS4 added to the high-fat diets on selected glucose augmentation of insulin secretion. Interactions of gastric inhibitory biochemical parameters in Wistar rats. Rocz. Panstw. Zakl. Hig. 64, 19–24. polypeptide with ambient glucose and insulin levels. J. Clin. Invest. 62, 152–161. Callaway, E. (2015). Microbiome privacy risk. Nature 521:136. doi: 10.1172/JCI109100 doi: 10.1038/521136a Anhe, F. F., Roy, D., Pilon, G., Dudonne, S., Matamoros, S., Varin, T. V., Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., et al. et al. (2015a). A polyphenol-rich cranberry extract protects from diet-induced (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes obesity, insulin resistance and intestinal inflammation in association with 56, 1761–1772. doi: 10.2337/db06-1491 increased Akkermansia spp. population in the gut microbiota of mice. Gut 64, Cani, P. D., Possemiers, S., Van de Wiele, T., Guiot, Y., Everard, A., Rottier, O., et al. 872–883. doi: 10.1136/gutjnl-2014-307142 (2009). Changes in gut microbiota control inflammation in obese mice through Anhe, F. F., Varin, T. V., Le Barz, M., Desjardins, Y., Levy, E., Roy, D., et al. a mechanism involving GLP-2-driven improvement of gut permeability. Gut (2015b). Gut microbiota dysbiosis in obesity-linked metabolic diseases and 58, 1091–1103. doi: 10.1136/gut.2008.165886 prebiotic potential of polyphenol-rich extracts. Curr. Obes. Rep. 4, 389–400. Caputo, A., Lagier, J. C., Azza, S., Robert, C., Mouelhi, D., Fournier, P. E., et al. doi: 10.1007/s13679-015-0172-9 (2016). Microvirga massiliensis sp. nov., the human commensal with the largest Backhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., et al. (2004). genome. Microbiol.Open 5, 307–322. doi: 10.1002/mbo3.329 The gut microbiota as an environmental factor that regulates fat storage. Proc. Carding, S., Verbeke, K., Vipond, D. T., Corfe, B. M., and Owen, L. J. (2015). Natl. Acad. Sci. U.S.A. 101, 15718–15723. doi: 10.1073/pnas.0407076101 Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 26:26191. Bäckhed, F., Roswall, J., Peng, Y., Feng, Q., Jia, H., Kovatcheva-Datchary, P., et al. doi: 10.3402/mehd.v26.26191 (2015). Dynamics and stabilization of the human gut microbiome during the Cardona, F., Andres-Lacueva, C., Tulipani, S., Tinahones, F. J., and Queipo- first year of life. Cell Host Microbe 17, 690–703. doi: 10.1016/j.chom.2015.04.004 Ortuno, M. I. (2013). Benefits of polyphenols on gut microbiota Bahadoran, Z., Mirmiran, P., and Azizi, F. (2013). Dietary polyphenols as potential and implications in human health. J. Nutr. Biochem. 24, 1415–1422. nutraceuticals in management of diabetes: a review. J. Diabetes Metab. Disord. doi: 10.1016/j.jnutbio.2013.05.001 12:43. doi: 10.1186/2251-6581-12-43 Carmody, R. N., Gerber, G. K., Luevano, J. M. Jr., Gatti, D. M., Somes, L., Svenson, Baothman, O. A., Zamzami, M. A., Taher, I., Abubaker, J., and Abu-Farha, M. K. L., et al. (2015). Diet dominates host genotype in shaping the murine gut (2016). The role of Gut Microbiota in the development of obesity and Diabetes. microbiota. Cell Host Microbe 17, 72–84. doi: 10.1016/j.chom.2014.11.010 Lipids Health Dis. 15:108. doi: 10.1186/s12944-016-0278-4 Carvalho, B. M., Guadagnini, D., Tsukumo, D. M., Schenka, A. A., Latuf-Filho, Baraldes, M. A., Domingo, P., Barrio, J. L., Pericas, R., Gurgui, M., and Vazquez, P., Vassallo, J., et al. (2012). Modulation of gut microbiota by antibiotics G. (2000). Meningitis due to Neisseria subflava: case report and review. Clin. improves insulin signalling in high-fat fed mice. Diabetologia 55, 2823–2834. Infect. Dis. 30, 615–617. doi: 10.1086/313700 doi: 10.1007/s00125-012-2648-4 Baron, E. J., Summanen, P., Downes, J., Roberts, M. C., Wexler, H., and Finegold, Cavicchioli, R. (2011). Archaea–timeline of the third domain. Nat. Rev. Microbiol. S. M. (1989). Bilophila wadsworthia, gen. nov. and sp. nov., a unique gram- 9, 51–61. doi: 10.1038/nrmicro2482 negative anaerobic rod recovered from appendicitis specimens and human Chan, C., Hyslop, C. M., Shrivastava, V., Ochoa, A., Reimer, R. A., and Huang, C. faeces. J. Gen. Microbiol. 135, 3405–3411. doi: 10.1099/00221287-135-12-3405 (2016). Oligofructose as an adjunct in treatment of diabetes in NOD mice. Sci. Bartelt, A., Bruns, O. T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., et al. Rep. 6:37627. doi: 10.1038/srep37627 (2011). Brown adipose tissue activity controls triglyceride clearance. Nat. Med. Cherbut, C., Ferrier, L., Roze, C., Anini, Y., Blottiere, H., Lecannu, G., et al. (1998). 17, 200–205. doi: 10.1038/nm.2297 Short-chain fatty acids modify colonic motility through nerves and polypeptide Beaumont, M., Andriamihaja, M., Lan, A., Khodorova, N., Audebert, M., Blouin, YY release in the rat. Am. J. Physiol. 275(6 Pt 1), G1415–G1422. J. M., et al. (2016). Detrimental effects for colonocytes of an increased exposure Chung, S., Yao, H., Caito, S., Hwang, J.-W., Arunachalam, G., and Rahman, I. to luminal hydrogen sulfide: the adaptive response. Free Radic. Biol. Med. 93, (2010). Regulation of SIRT1 in cellular functions: role of polyphenols. Arch. 155–164. doi: 10.1016/j.freeradbiomed.2016.01.028 Biochem. Biophys. 501, 79–90. doi: 10.1016/j.abb.2010.05.003 Belizário, J. E., and Napolitano, M. (2015). Human microbiomes and their roles Clarke, S. T., Green-Johnson, J. M., Brooks, S. P., Ramdath, D. D., Bercik, P., in dysbiosis, common diseases, and novel therapeutic approaches. Front. Avila, C., et al. (2016). beta2-1 Fructan supplementation alters host immune Microbiol. 6:1050. doi: 10.3389/fmicb.2015.01050 responses in a manner consistent with increased exposure to microbial Belkaid, Y., and Hand, T. W. (2014). Role of the microbiota in immunity and components: results from a double-blinded, randomised, cross-over study inflammation. Cell 157, 121–141. doi: 10.1016/j.cell.2014.03.011 in healthy adults. Br. J. Nutr. 115, 1748–1759. doi: 10.1017/S00071145160 Belzer, C., and de Vos, W. M. (2012). Microbes inside–from diversity to function: 00908 the case of Akkermansia. ISME J. 6, 1449–1458. doi: 10.1038/ismej.2012.6 Coppo, E., and Marchese, A. (2014). Antibacterial activity of polyphenols. Curr. Berding, K., and Donovan, S. M. (2016). Microbiome and nutrition in autism Pharm. Biotechnol. 15, 380–390. doi: 10.2174/138920101504140825121142 spectrum disorder: current knowledge and research needs. Nutr. Rev. 74, Corless, C. E., Guiver, M., Borrow, R., Edwards-Jones, V., Fox, A. J., and 723–736. doi: 10.1093/nutrit/nuw048 Kaczmarski, E. B. (2001). Simultaneous detection of Neisseria meningitidis,

Frontiers in Pharmacology | www.frontiersin.org 22 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Haemophilus influenzae, and Streptococcus pneumoniae in suspected cases Derrien, M., Vaughan, E. E., Plugge, C. M., and de Vos, W. M. (2004). Akkermansia of meningitis and septicemia using real-time PCR. J. Clin. Microbiol. 39, muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading 1553–1558. doi: 10.1128/JCM.39.4.1553-1558.2001 bacterium. Int. J. Syst. Evol. Microbiol. 54(Pt 5), 1469–1476. doi: 10.1099/ijs.0. Cox, R. A., and Garcia-Palmieri, M. R. (1990). “Cholesterol, triglycerides, and 02873-0 associated lipoproteins,” in Clinical Methods: The History, Physical, and Duda-Chodak, A., Tarko, T., Satora, P., and Sroka, P. (2015). Interaction of dietary Laboratory Examinations, 3rd Edn., eds H. K. Walker, W. D. Hall, and J. W. compounds, especially polyphenols, with the intestinal microbiota: a review. Hurst (Boston, MA: Butterworths), 153–160. Eur. J. Nutr. 54, 325–341. doi: 10.1007/s00394-015-0852-y Cummings, J. H., and Stephen. A. M. (2007). Carbohydrate terminology Duncan, S. H., Hold, G. L., Harmsen, H. J., Stewart, C. S., and Flint, H. J. and classification. Eur. J. Clin. Nutr. 61(Suppl. 1), S5–S18. (2002). Growth requirements and fermentation products of Fusobacterium doi: 10.1038/sj.ejcn.1602936 prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii D’Aimmo, M. R., Mattarelli, P., Biavati, B., Carlsson, N. G., and Andlid, T. (2012). gen. nov., comb. nov. Int. J. Syst. Evol. Microbiol. 52(Pt 6), 2141–2146. The potential of bifidobacteria as a source of natural folate. J. Appl. Microbiol. doi: 10.1099/00207713-52-6-2141 112, 975–984. doi: 10.1111/j.1365-2672.2012.05261.x Duranti, S., Milani, C., Lugli, G. A., Mancabelli, L., Turroni, F., Ferrario, Dalton, H. W. (1951). Implantation of B. coli into the human intestine. Ir. J. Med. C., et al. (2016). Evaluation of genetic diversity among strains of the Sci. 308, 384–386. doi: 10.1007/BF02956866 human gut commensal Bifidobacterium adolescentis. Sci. Rep. 6:23971. Daubioul, C., Rousseau, N., Demeure, R., Gallez, B., Taper, H., Declerck, B., et al. doi: 10.1038/srep23971 (2002). Dietary fructans, but not cellulose, decrease triglyceride accumulation Edholm, T., Degerblad, M., Gryback, P., Hilsted, L., Holst, J. J., Jacobsson, H., in the liver of obese Zucker fa/fa rats. J. Nutr. 132, 967–973. et al. (2010). Differential incretin effects of GIP and GLP-1 on gastric emptying, Davis, C. P. (1996). “Normal flora,” in Medical Microbiology, 4th Edn., ed S. Baron appetite, and insulin-glucose homeostasis. Neurogastroenterol. Motil. 22, (Galveston, TX: University of Texas Medical Branch). Available online at: 1191–1200. doi: 10.1111/j.1365-2982.2010.01554.x https://www.ncbi.nlm.nih.gov/books/NBK7617/ Eggerth, A. H. (1935). The gram-positive non-spore-bearing anaerobic bacilli of De Angelis, M., Piccolo, M., Vannini, L., Siragusa, S., De Giacomo, A., human feces. J. Bacteriol. 30, 277–299. Serrazzanetti, D. I., et al. (2013). Fecal microbiota and metabolome of children Eggerth, A. H., and Gagnon, B. H. (1933). The bacteroides of human feces. J. with autism and pervasive developmental disorder not otherwise specified. Bacteriol. 25, 389–413. PLoS ONE 8:e76993. doi: 10.1371/journal.pone.0076993 Eid, H. M., and Haddad, P. S. (2017). The antidiabetic potential of de Deckere, E. A., Kloots, W. J., and van Amelsvoort, J. M. (1993). Resistant starch quercetin: underlying mechanisms. Curr. Med. Chem. 24, 355–364. decreases serum total cholesterol and triacylglycerol concentrations in rats. J. doi: 10.2174/0929867323666160909153707 Nutr. 123, 2142–2151. Eid, H. M., Nachar, A., Thong, F., Sweeney, G., and Haddad, P. S. Deacon, C. F. (2004). Therapeutic strategies based on glucagon-like peptide 1. (2015). The molecular basis of the antidiabetic action of quercetin in Diabetes 53, 2181–2189. doi: 10.2337/diabetes.53.9.2181 cultured skeletal muscle cells and hepatocytes. Pharmacogn. Mag. 11, 74–81. Delgado, S., Cabrera-Rubio, R., Mira, A., Suarez, A., and Mayo, B. doi: 10.4103/0973-1296.149708 (2013). Microbiological survey of the human gastric ecosystem using Ellinger, S., and Stehle, P. (2016). Impact of cocoa consumption on inflammation culturing and pyrosequencing methods. Microb. Ecol. 65, 763–772. processes—a critical review of randomized controlled trials. Nutrients 8:321. doi: 10.1007/s00248-013-0192-5 doi: 10.3390/nu8060321 Delzenne, N. M., and Cani, P. D. (2011). Gut microbiota and the Engstrand, L., and Lindberg, M. (2013). Helicobacter pylori and the pathogenesis of insulin resistance. Curr. Diabetes Rep. 11, 154–159. gastric microbiota. Best Pract. Res. Clin. Gastroenterol. 27, 39–45. doi: 10.1007/s11892-011-0191-1 doi: 10.1016/j.bpg.2013.03.016 Delzenne, N. M., Cani, P. D., Daubioul, C., and Neyrinck, A. M. (2005). Impact of Etxeberria, U., Arias, N., Boque, N., Macarulla, M. T., Portillo, M. P., Martinez, J. inulin and oligofructose on gastrointestinal peptides. Br. J. Nutr. 93(Suppl. 1), A., et al. (2015). Reshaping faecal gut microbiota composition by the intake S157–S161. doi: 10.1079/bjn20041342 of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. J. Nutr. Delzenne, N. M., Cani, P. D., Daubioul, C., and Neyrinck, A. M. (2007). Impact Biochem. 26, 651–660. doi: 10.1016/j.jnutbio.2015.01.002 of inulin and oligofructose on gastrointestinal peptides. Br. J. Nutr. 93:S157. Evans, D. F., Pye, G., Bramley, R., Clark, A. G., Dyson, T. J., and Hardcastle, J. doi: 10.1079/BJN20041342 D. (1988). Measurement of gastrointestinal pH profiles in normal ambulant Delzenne, N. M., Daubioul, C., Neyrinck, A., Lasa, M., and Taper, H. S. (2002). human subjects. Gut 29, 1035–1041. doi: 10.1136/gut.29.8.1035 Inulin and oligofructose modulate lipid metabolism in animals: review of Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J. P., Druart, C., Bindels, L. B., et al. biochemical events and future prospects. Br. J. Nutr. 87(Suppl. 2), S255–S259. (2013). Cross-talk between Akkermansia muciniphila and intestinal epithelium doi: 10.1079/BJN/2002545 controls diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 110, 9066–9071. den Besten, G., Bleeker, A., Gerding, A., van Eunen, K., Havinga, R., van Dijk, T. doi: 10.1073/pnas.1219451110 H., et al. (2015). Short-chain fatty acids protect against high-fat diet-induced Fagundes Neto, U., Patricio, F. R., Wehba, J., Reis, M. H., Gianotti, O. F., and obesity via a PPARgamma-dependent switch from lipogenesis to fat oxidation. Trabulsi, L. R. (1979). An Escherichia coli strain that causes diarrhea by invasion Diabetes 64, 2398–2408. doi: 10.2337/db14-1213 of the small intestinal mucosa and induces monosaccharide intolerance. Arq. den Besten, G., Havinga, R., Bleeker, A., Rao, S., Gerding, A., van Eunen, K., Gastroenterol. 16, 205–208. et al. (2014). The short-chain fatty acid uptake fluxes by mice on a guar Falcone, E. L., Abusleme, L., Swamydas, M., Lionakis, M. S., Ding, L., Hsu, A. P., gum supplemented diet associate with amelioration of major biomarkers of et al. (2016). Colitis susceptibility in p47(phox−/−) mice is mediated by the the metabolic syndrome. PLoS ONE 9:e107392. doi: 10.1371/journal.pone. microbiome. Microbiome 4, 13. doi: 10.1186/s40168-016-0159-0 0107392 Fändriks, L. (2017). Roles of the gut in the metabolic syndrome: an overview. J. den Besten, G., Lange, K., Havinga, R., van Dijk, T. H., Gerding, A., van Eunen, K., Intern. Med. 281, 319–336. doi: 10.1111/joim.12584 et al. (2013a). Gut-derived short-chain fatty acids are vividly assimilated into Finegold, S. M., Attebery, H. R., and Sutter, V. L. (1974). Effect of diet on human host carbohydrates and lipids. Am. J. Physiol. Gastrointest. Liver Physiol. 305, fecal flora: comparison of Japanese and American diets. Am. J. Clin. Nutr. 27, G900–G910. doi: 10.1152/ajpgi.00265.2013 1456–1469. den Besten, G., van Eunen, K., Groen, A. K., Venema, K., Reijngoud, D.-J., and Forester, S. C., and Waterhouse, A. L. (2010). Gut metabolites of anthocyanins, Bakker, B. M. (2013b). The role of short-chain fatty acids in the interplay gallic acid, 3-O-methylgallic acid, and 2,4,6-trihydroxybenzaldehyde, inhibit between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, cell proliferation of Caco-2 cells. J. Agric. Food Chem. 58, 5320–5327. 2325–2340. doi: 10.1194/jlr.R036012 doi: 10.1021/jf9040172 Denis, M. C., Roy, D., Yeganeh, P. R., Desjardins, Y., Varin, T., Haddad, Freeland, K. R., and Wolever, T. M. (2010). Acute effects of intravenous N., et al. (2016). Apple peel polyphenols: a key player in the prevention and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, and treatment of experimental inflammatory bowel disease. Clin. Sci. 130, adiponectin and tumour necrosis factor-alpha. Br. J. Nutr. 103, 460–466. 2217–2237. doi: 10.1042/CS20160524 doi: 10.1017/S0007114509991863

Frontiers in Pharmacology | www.frontiersin.org 23 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Fu, J., Bonder, M. J., Cenit, M. C., Tigchelaar, E. F., Maatman, A., Dekens, Hashmi, A., Naeem, N., Farooq, Z., Masood, S., Iqbal, S., and Naseer, J. A., et al. (2015). The gut microbiome contributes to a substantial R. (2016). Effect of prebiotic galacto-oligosaccharides on serum lipid proportion of the variation in blood lipids. Circ. Res. 117, 817–824. profile of hypercholesterolemics. Probiotics Antimicrob. Proteins 8, 19–30. doi: 10.1161/CIRCRESAHA.115.306807 doi: 10.1007/s12602-016-9206-1 Fukino, Y., Shimbo, M., Aoki, N., Okubo, T., and Iso, H. (2005). Randomized Hayashi, H., Sakamoto, M., and Benno, Y. (2002). Phylogenetic analysis controlled trial for an effect of green tea consumption on insulin of the human gut microbiota using 16S rDNA clone libraries and resistance and inflammation markers. J. Nutr. Sci. Vitaminol. 51, 335–342. strictly anaerobic culture-based methods. Microbiol. Immunol. 46, 535–548. doi: 10.3177/jnsv.51.335 doi: 10.1111/j.1348-0421.2002.tb02731.x Gaci, N., Borrel, G., Tottey, W., O’Toole, P. W., and Brugere, J. F. (2014). Archaea Hayashi, H., Shibata, K., Sakamoto, M., Tomita, S., and Benno, Y. (2007). Prevotella and the human gut: new beginning of an old story. World J. Gastroenterol. 20, copri sp. nov. and Prevotella stercorea sp. nov., isolated from human faeces. Int. 16062–16078. doi: 10.3748/wjg.v20.i43.16062 J. Syst. Evol. Microbiol. 57(Pt 5), 941–946. doi: 10.1099/ijs.0.64778-0 Ganesh, B. P., Klopfleisch, R., Loh, G., and Blaut, M. (2013). Commensal Hayashi, H., Takahashi, R., Nishi, T., Sakamoto, M., and Benno, Y. (2005). Akkermansia muciniphila exacerbates gut inflammation in Salmonella Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human Typhimurium-infected gnotobiotic mice. PLoS ONE 8:e74963. colonic microbiota using 16S rRNA gene libraries and terminal restriction doi: 10.1371/journal.pone.0074963 fragment length polymorphism. J. Med. Microbiol. 54(Pt 11), 1093–1101. Gao, S., and Hu, M. (2010). Bioavailability challenges associated with doi: 10.1099/jmm.0.45935-0 development of anti-cancer phenolics. Mini Rev. Med. Chem. 10, 550–567. Hidalgo, M., Oruna-Concha, M. J., Kolida, S., Walton, G. E., Kallithraka, S., doi: 10.2174/138955710791384081 Spencer, J. P., et al. (2012). Metabolism of anthocyanins by human gut Geraylou, Z., Souffreau, C., Rurangwa, E., Maes, G. E., Spanier, K. I., Courtin, C. microflora and their influence on gut bacterial growth. J. Agric. Food Chem. M., et al. (2013). Prebiotic effects of arabinoxylan oligosaccharides on juvenile 60, 3882–3890. doi: 10.1021/jf3002153 Siberian sturgeon (Acipenser baerii) with emphasis on the modulation of the Hiippala, K., Kainulainen, V., Kalliomaki, M., Arkkila, P., and Satokari, gut microbiota using 454 pyrosequencing. FEMS Microbiol. Ecol. 86, 357–371. R. (2016). Mucosal prevalence and interactions with the epithelium doi: 10.1111/1574-6941.12169 indicate commensalism of Sutterella spp. Front. Microbiol. 7:1706. Gerritsen, J., Smidt, H., Rijkers, G. T., and de Vos, W. M. (2011). Intestinal doi: 10.3389/fmicb.2016.01706 microbiota in human health and disease: the impact of probiotics. Genes Nutr. Hira, T., Ikee, A., Kishimoto, Y., Kanahori, S., and Hara, H. (2015). 6, 209–240. doi: 10.1007/s12263-011-0229-7 Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and Ghouri, Y. A., Richards, D. M., Rahimi, E. F., Krill, J. T., Jelinek, K. A., and production together with glucose tolerance in rats. Br. J. Nutr. 114, 34–42. DuPont, A. W. (2014). Systematic review of randomized controlled trials of doi: 10.1017/S0007114514004322 probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin. Exp. Holdeman, L. V., Good, I. J., and Moore, W. E. (1976). Human fecal flora: variation Gastroenterol. 7, 473–487. doi: 10.2147/CEG.S27530 in bacterial composition within individuals and a possible effect of emotional Gondalia, S. V., Palombo, E. A., Knowles, S. R., Cox, S. B., Meyer, D., and Austin, stress. Appl. Environ. Microbiol. 31, 359–375. D. W. (2012). Molecular characterisation of gastrointestinal microbiota of Hollman, P. C., de Vries, J. H., van Leeuwen, S. D., Mengelers, M. J., and Katan, M. children with autism (with and without gastrointestinal dysfunction) and their B. (1995). Absorption of dietary quercetin glycosides and quercetin in healthy neurotypical siblings. Autism Res. 5, 419–427. doi: 10.1002/aur.1253 ileostomy volunteers. Am. J. Clin. Nutr. 62, 1276–1282. Gonthier, M. P., Verny, M. A., Besson, C., Remesy, C., and Scalbert, A. (2003). Holmes, E., Loo, R. L., Stamler, J., Bictash, M., Yap, I. K., Chan, Q., et al. (2008). Chlorogenic acid bioavailability largely depends on its metabolism by the gut Human metabolic phenotype diversity and its association with diet and blood microflora in rats. J. Nutr. 133, 1853–1859. pressure. Nature 453, 396–400. doi: 10.1038/nature06882 Goodrich, J. K., Waters, J. L., Poole, A. C., Sutter, J. L., Koren, O., Blekhman, R., Holst, J. J. (2007). The physiology of glucagon-like peptide 1. Physiol. Rev. 87, et al. (2014). Human genetics shape the gut microbiome. Cell 159, 789–799. 1409–1439. doi: 10.1152/physrev.00034.2006 doi: 10.1016/j.cell.2014.09.053 Hong, K. B., Kim, J. H., Kwon, H. K., Han, S. H., Park, Y., and Grosso, G., Stepaniak, U., Micek, A., Stefler, D., Bobak, M., and Paj ˛ak, A. Suh, H. J. (2016). Evaluation of prebiotic effects of high-purity (2017). Dietary polyphenols are inversely associated with metabolic syndrome galactooligosaccharides in vitro and in vivo. Food Technol. Biotechnol. 54, in Polish adults of the HAPIEE study. Eur. J. Nutr. 56, 1409–1420. 156–163. doi: 10.17113/ftb.54.02.16.4292 doi: 10.1007/s00394-016-1187-z Hong, K., Jang, K. H., Lee, J. C., Kim, S., Kim, M. K., Lee, I. Y., et al. (2005). Bacterial Grundy, S. M., Brewer, H. B., Cleeman, J. I., Smith, S. C., and Lenfant, beta-glucan exhibits potent hypoglycemic activity via decrease of serum lipids C. (2004). Definition of metabolic syndrome. Circulation 109:433. and adiposity, and increase of UCP mRNA expression. J. Microbiol. Biotechnol. doi: 10.1161/01.CIR.0000111245.75752.C6 15:8. Guarner, F., and Malagelada, J. R. (2003). Gut flora in health and disease. Lancet Hooda, S., Boler, B. M., Serao, M. C., Brulc, J. M., Staeger, M. A., Boileau, T. 361, 512–519. doi: 10.1016/S0140-6736(03)12489-0 W., et al. (2012). 454 pyrosequencing reveals a shift in fecal microbiota of Hajiaghaalipour, F., Khalilpourfarshbafi, M., and Arya, A. (2015). Modulation of healthy adult men consuming polydextrose or soluble corn fiber. J. Nutr. 142, glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus. 1259–1265. doi: 10.3945/jn.112.158766 Int. J. Biol. Sci. 11, 508–524. doi: 10.7150/ijbs.11241 Hooper, L., Kroon, P. A., Rimm, E. B., Cohn, J. S., Harvey, I., Le Cornu, K. Halliwell, B., Rafter, J., and Jenner, A. (2005). Health promotion by flavonoids, A., et al. (2008). Flavonoids, flavonoid-rich foods, and cardiovascular risk: a tocopherols, tocotrienols, and other phenols: direct or indirect effects? meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 88, 38–50. Antioxidant or not? Am. J. Clin. Nutr. 81(1 Suppl.), 268S–276S. Hopkins, M. J., Sharp, R., and Macfarlane, G. T. (2001). Age and disease related Hamilton, M. K., Boudry, G., Lemay, D. G., and Raybould, H. E. (2015). Changes changes in intestinal bacterial populations assessed by cell culture, 16S rRNA in intestinal barrier function and gut microbiota in high-fat diet-fed rats are abundance, and community cellular fatty acid profiles. Gut 48, 198–205. dynamic and region dependent. Am. J. Physiol. Gastrointest. Liver Physiol. 308, doi: 10.1136/gut.48.2.198 G840–G851. doi: 10.1152/ajpgi.00029.2015 Horz, H. P. (2015). Archaeal lineages within the human microbiome: absent, rare Hanhineva, K., Torronen, R., Bondia-Pons, I., Pekkinen, J., Kolehmainen, M., or elusive? Life (Basel) 5, 1333–1345. doi: 10.3390/life5021333 Mykkanen, H., et al. (2010). Impact of dietary polyphenols on carbohydrate Hosseini, E., Grootaert, C., Verstraete, W., and Van de Wiele, T. (2011). Propionate metabolism. Int. J. Mol. Sci. 11, 1365–1402. doi: 10.3390/ijms11041365 as a health-promoting microbial metabolite in the human gut. Nutr. Rev. 69, Hartman, A. L., Lough, D. M., Barupal, D. K., Fiehn, O., Fishbein, T., Zasloff, 245–258. doi: 10.1111/j.1753-4887.2011.00388.x M., et al. (2009). Human gut microbiome adopts an alternative state following Hou, C. C., Lai, C. C., Liu, W. L., Chao, C. M., Chiu, Y. H., and Hsueh, P. R. (2011). small bowel transplantation. Proc. Natl. Acad. Sci. U.S.A. 106, 17187–17192. Clinical manifestation and prognostic factors of non-cholerae Vibrio infections. doi: 10.1073/pnas.0904847106 Eur. J. Clin. Microbiol. Infect. Dis. 30, 819–824. doi: 10.1007/s10096-011-1162-9 Hasegawa, H., Sung, J. H., and Benno, Y. (1997). Role of human intestinal Hoverstad, T., Fausa, O., Bjorneklett, A., and Bohmer, T. (1984). Short- Prevotella oris in hydrolyzing ginseng saponins. Planta Med. 63, 436–440. chain fatty acids in the normal human feces. Scand. J. Gastroenterol. 19, doi: 10.1055/s-2006-957729 375–381.

Frontiers in Pharmacology | www.frontiersin.org 24 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Hoyles, L., Honda, H., Logan, N. A., Halket, G., La Ragione, R. M., and Knapp, B. A., Seeber, J., Rief, A., Meyer, E., and Insam, H. (2010). Bacterial McCartney, A. L. (2012). Recognition of greater diversity of Bacillus community composition of the gut microbiota of Cylindroiulus fulviceps species and related bacteria in human faeces. Res. Microbiol. 163, 3–13. (diplopoda) as revealed by molecular fingerprinting and cloning. Folia doi: 10.1016/j.resmic.2011.10.004 Microbiol. (Praha). 55, 489–496. doi: 10.1007/s12223-010-0081-y Hsu, C. K., Liao, J. W., Chung, Y. C., Hsieh, C. P., and Chan, Y. C. Koenig, J. E., Spor, A., Scalfone, N., Fricker, A. D., Stombaugh, J., Knight, (2004). Xylooligosaccharides and fructooligosaccharides affect the intestinal R., et al. (2011). Succession of microbial consortia in the developing microbiota and precancerous colonic lesion development in rats. J. Nutr. 134, infant gut microbiome. Proc. Natl. Acad. Sci. U.S.A. 108(Suppl.), 4578–4585. 1523–1528. doi: 10.1073/pnas.1000081107 Hu, Y., Le Leu, R. K., Christophersen, C. T., Somashekar, R., Conlon, M. A., Meng, Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., et al. X. Q., et al. (2016). Manipulation of the gut microbiota using resistant starch (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, is associated with protection against colitis-associated colorectal cancer in rats. promotes atherosclerosis. Nat. Med. 19, 576–585. doi: 10.1038/nm.3145 Carcinogenesis 37, 366–375. doi: 10.1093/carcin/bgw019 Kok, N., Roberfroid, M., and Delzenne, N. (1996). Dietary oligofructose modifies Hugon, P., Lagier, J. C., Colson, P., Bittar, F., and Raoult, D. (2016). the impact of fructose on hepatic triacylglycerol metabolism. Metab. Clin. Exp. Repertoire of human gut microbes. Microb. Pathog. 106, 103–112. 45, 1547–1550. doi: 10.1016/S0026-0495(96)90186-9 doi: 10.1016/j.micpath.2016.06.020 Koleva, P. T., Valcheva, R. S., Sun, X., Ganzle, M. G., and Dieleman, L. A. Human Microbiome Project Consortium (2012). Structure, function and (2012). Inulin and fructo-oligosaccharides have divergent effects on colitis and diversity of the healthy human microbiome. Nature 486, 207–214. commensal microbiota in HLA-B27 transgenic rats. Br. J. Nutr. 108, 1633–1643. doi: 10.1038/nature11234 doi: 10.1017/S0007114511007203 Janda, J. M., and Abbott, S. L. (1998). Evolving concepts regarding the Koren, O., Spor, A., Felin, J., Fak, F., Stombaugh, J., Tremaroli, V., et al. (2011). genus Aeromonas: an expanding Panorama of species, disease presentations, Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. and unanswered questions. Clin. Infect. Dis. 27, 332–344. doi: 10.1086/ Natl. Acad. Sci. U.S.A. 108(Suppl. 1), 4592–4598. doi: 10.1073/pnas.1011383107 514652 Kostic, A. D., Gevers, D., Pedamallu, C. S., Michaud, M., Duke, F., Earl, A. M., Janda, J. M., and Abbott, S. L. (2010). The genus Aeromonas: taxonomy, et al. (2012). Genomic analysis identifies association of Fusobacterium with pathogenicity, and infection. Clin. Microbiol. Rev. 23, 35–73. colorectal carcinoma. Genome Res. 22, 292–298. doi: 10.1101/gr.126573.111 doi: 10.1128/CMR.00039-09 Kumar, S., and Pandey, A. K. (2013). Chemistry and biological activities of Johnston, K., Sharp, P., Clifford, M., and Morgan, L. (2005). Dietary polyphenols flavonoids: an overview. Sci. World J. 2013, 16. doi: 10.1155/2013/162750 decrease glucose uptake by human intestinal Caco-2 cells. FEBS Lett. 579, Kwon, O., Eck, P., Chen, S., Corpe, C. P., Lee, J. H., Kruhlak, M., et al. (2007). 1653–1657. doi: 10.1016/j.febslet.2004.12.099 Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J. Kaakoush, N. O., Day, A. S., Huinao, K. D., Leach, S. T., Lemberg, D. A., Dowd, S. 21, 366–377. doi: 10.1096/fj.06-6620com E., et al. (2012). Microbial dysbiosis in pediatric patients with crohn’s disease. J. Lafay, S., and Gil-Izquierdo, A. (2008). Bioavailability of phenolic acids. Clin. Microbiol. 50, 3258–3266. doi: 10.1128/JCM.01396-12 Phytochem. Rev. 7:301. doi: 10.1007/s11101-007-9077-x Kageyama, A., Benno, Y., and Nakase, T. (1999). Phylogenetic and phenotypic Lagier, J. C., Armougom, F., Million, M., Hugon, P., Pagnier, I., Robert, C., et al. evidence for the transfer of Eubacterium aerofaciens to the genus Collinsella (2012). Microbial culturomics: paradigm shift in the human gut microbiome as Collinsella aerofaciens gen. nov., comb. nov. Int. J. Syst. Bacteriol. 49(Pt 2), study. Clin. Microbiol. Infect. 18, 1185–1193. doi: 10.1111/1469-0691.12023 557–565. doi: 10.1099/00207713-49-2-557 Larrosa, M., Gonzalez-Sarrias, A., Yanez-Gascon, M. J., Selma, M. V., Azorin- Kaji, I., Karaki, S.-I., and Kuwahara, A. (2014). Short-chain fatty acid receptor Ortuno, M., Toti, S., et al. (2010). Anti-inflammatory properties of a and its contribution to glucagon-like peptide-1 release. Digestion 89, 31–36. pomegranate extract and its metabolite urolithin-A in a colitis rat model and doi: 10.1159/000356211 the effect of colon inflammation on phenolic metabolism. J. Nutr. Biochem. 21, Kaliannan, K., Wang, B., Li, X. Y., Kim, K. J., and Kang, J. X. (2015). A host- 717–725. doi: 10.1016/j.jnutbio.2009.04.012 microbiome interaction mediates the opposing effects of omega-6 and omega-3 Larsbrink, J., Rogers, T. E., Hemsworth, G. R., McKee, L. S., Tauzin, A. S., Spadiut, fatty acids on metabolic endotoxemia. Sci. Rep. 5:11276. doi: 10.1038/srep11276 O., et al. (2014). A discrete genetic locus confers xyloglucan metabolism in Kaur, J. (2014). A comprehensive review on metabolic syndrome. Cardiol. Res. select human gut Bacteroidetes. Nature 506, 498–502. doi: 10.1038/nature12907 Pract. 2014:943162. doi: 10.1155/2014/943162 Larsen, N., Vogensen, F. K., van den Berg, F. W., Nielsen, D. S., Andreasen, Kaushik, S. J., Medale, F., Fauconneau, B., and Blanc, D. (1989). Effect A. S., Pedersen, B. K., et al. (2010). Gut microbiota in human adults of digestible carbohydrates on protein/energy utilization and on glucose with type 2 diabetes differs from non-diabetic adults. PLoS ONE 5:e9085. metabolism in rainbow trout (Salmo gairdneri R.). Aquaculture 79, 63–74. doi: 10.1371/journal.pone.0009085 doi: 10.1016/0044-8486(89)90446-8 Lau, J. T., Whelan, F. J., Herath, I., Lee, C. H., Collins, S. M., Bercik, P., et al. (2016). Kawabata, K., Sugiyama, Y., Sakano, T., and Ohigashi, H. (2013). Flavonols Capturing the diversity of the human gut microbiota through culture-enriched enhanced production of anti-inflammatory substance(s) by Bifidobacterium molecular profiling. Genome Med. 8:72. doi: 10.1186/s13073-016-0327-7 adolescentis: prebiotic actions of galangin, quercetin, and fisetin. Biofactors 39, Lawson, P. A., and Finegold, S. M. (2015). Reclassification of Ruminococcus 422–429. doi: 10.1002/biof.1081 obeum as Blautiaobeum comb. nov. Int. J. Syst. Evol. Microbiol. 65, 789–793. Keenan, M. J., Zhou, J., Hegsted, M., Pelkman, C., Durham, H. A., Coulon, D. B., doi: 10.1099/ijs.0.000015 et al. (2015). Role of resistant starch in improving gut health, adiposity, and Le Barz, M., Anhe, F. F., Varin, T. V., Desjardins, Y., Levy, E., Roy, D., et al. (2015). insulin resistance. Adv. Nutr. 6, 198–205. doi: 10.3945/an.114.007419 Probiotics as complementary treatment for metabolic disorders. Diabetes Kellett, G. L., and Helliwell, P. A. (2000). The diffusive component of intestinal Metab. J. 39, 291–303. doi: 10.4093/dmj.2015.39.4.291 glucose absorption is mediated by the glucose-induced recruitment of Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., et al. GLUT2 to the brush-border membrane. Biochem. J. 350(Pt 1), 155–162. (2013). Richness of human gut microbiome correlates with metabolic markers. doi: 10.1042/bj3500155 Nature 500, 541–546. doi: 10.1038/nature12506 Keshav, S. (2006). Paneth cells: leukocyte-like mediators of innate immunity in the LeBlanc, J. G., Milani, C., de Giori, G. S., Sesma, F., van Sinderen, intestine. J. Leukoc. Biol. 80, 500–508. doi: 10.1189/jlb.1005556 D., and Ventura, M. (2013). Bacteria as vitamin suppliers to their Khurana, S., Venkataraman, K., Hollingsworth, A., Piche, M., and Tai, T. C. (2013). host: a gut microbiota perspective. Curr. Opin. Biotechnol. 24, 160–168. Polyphenols: benefits to the cardiovascular system in health and in aging. doi: 10.1016/j.copbio.2012.08.005 Nutrients 5, 3779–3827. doi: 10.3390/nu5103779 Ley, R. E., Peterson, D. A., and Gordon, J. I. (2006). Ecological and evolutionary Kiatpapan, P., and Murooka, Y. (2002). Genetic manipulation system in forces shaping microbial diversity in the human intestine. Cell 124, 837–848. propionibacteria. J. Biosci. Bioeng. 93, 1–8. doi: 10.1016/S1389-1723(02) doi: 10.1016/j.cell.2006.02.017 80045-7 Li, A.-N., Li, S., Zhang, Y.-J., Xu, X.-R., Chen, Y.-M., and Li, H.-B. (2014). Kieffer, T. J., and Habener, J. F. (1999). The glucagon-like peptides. Endocr. Rev. Resources and biological activities of natural polyphenols. Nutrients 6, 20, 876–913. doi: 10.1210/edrv.20.6.0385 6020–6047. doi: 10.3390/nu6126020

Frontiers in Pharmacology | www.frontiersin.org 25 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Li, X.-X., Wong, G. L.-H., To, K.-F., Wong, V. W.-S., Lai, L. H., Chow, D. K.- Mestdagh, R., Dumas, M. E., Rezzi, S., Kochhar, S., Holmes, E., Claus, S. P., et al. L., et al. (2009). Bacterial microbiota profiling in gastritis without helicobacter (2012). Gut microbiota modulate the metabolism of brown adipose tissue in pylori infection or non-steroidal anti-inflammatory drug use. PLoS ONE mice. J. Proteome Res. 11, 620–630. doi: 10.1021/pr200938v 4:e7985. doi: 10.1371/journal.pone.0007985 Minot, S., Sinha, R., Chen, J., Li, H., Keilbaugh, S. A., Wu, G. D., et al. (2011). The Lim, M. Y., You, H. J., Yoon, H. S., Kwon, B., Lee, J. Y., Lee, S., et al. (2016). human gut virome: inter-individual variation and dynamic response to diet. The effect of heritability and host genetics on the gut microbiota and metabolic Genome Res. 21, 1616–1625. doi: 10.1101/gr.122705.111 syndrome. Gut. 66, 1031–1038. doi: 10.1136/gutjnl-2015-311326 Miquel, S., Martin, R., Rossi, O., Bermudez-Humaran, L. G., Chatel, J. M., Sokol, Lin, H. V., Frassetto, A., Kowalik, E. J. Jr., Nawrocki, A. R., Lu, M. M., Kosinski, H., et al. (2013). Faecalibacterium prausnitzii and human intestinal health. Curr. J. R., et al. (2012). Butyrate and propionate protect against diet-induced Opin. Microbiol. 16, 255–261. doi: 10.1016/j.mib.2013.06.003 obesity and regulate gut hormones via free fatty acid receptor 3-independent Modler, H. W. (1994). Bifidogenic factors—sources, metabolism and applications. mechanisms. PLoS ONE 7:e35240. doi: 10.1371/journal.pone.0035240 Int. Dairy J. 4, 383–407. doi: 10.1016/0958-6946(94)90055-8 Liu, F., Prabhakar, M., Ju, J., Long, H., and Zhou, H. W. (2016). Effect of inulin- Moore, W. E., and Holdeman, L. V. (1974). Human fecal flora: the normal flora of type fructans on blood lipid profile and glucose level: a systematic review and 20 Japanese-Hawaiians. Appl. Microbiol. 27, 961–979. meta-analysis of randomized controlled trials. Eur. J. Clin. Nutr. 71, 9–20. Morand, C., Levrat, M. A., Besson, C., Demigne, C., and Remesy, C. (1994). Effects doi: 10.1038/ejcn.2016.156 of a diet rich in resistant starch on hepatic lipid metabolism in the rat. J. Nutr. Liu, T. W., Cephas, K. D., Holscher, H. D., Kerr, K. R., Mangian, H. F., Biochem. 5, 138–144. doi: 10.1016/0955-2863(94)90085-X Tappenden, K. A., et al. (2016). Nondigestible fructans alter gastrointestinal Morotomi, M., Nagai, F., and Watanabe, Y. (2011). Parasutterella secunda sp. barrier function, gene expression, histomorphology, and the microbiota nov., isolated from human faeces and proposal of Sutterellaceae fam. nov. profiles of diet-induced obese C57BL/6J mice. J. Nutr. 146, 949–956. in the order Burkholderiales. Int. J. Syst. Evol. Microbiol. 61(Pt 3), 637–643. doi: 10.3945/jn.115.227504 doi: 10.1099/ijs.0.023556-0 Liu, Y. J., Zhan, J., Liu, X. L., Wang, Y., Ji, J., and He, Q. Q. (2014). Morotomi, M., Nagai, F., and Watanabe, Y. (2012). Description of Christensenella Dietary flavonoids intake and risk of type 2 diabetes: a meta-analysis of minuta gen. nov., sp. nov., isolated from human faeces, which forms a distinct prospective cohort studies. Clin. Nutr. 33, 59–63. doi: 10.1016/j.clnu.2013. branch in the order Clostridiales, and proposal of Christensenellaceae fam. nov. 03.011 Int. J. Syst. Evol. Microbiol. 62(Pt 1), 144–149. doi: 10.1099/ijs.0.026989-0 Liu, Z. M., Chen, Y. M., Ho, S. C., Ho, Y. P., and Woo, J. (2010). Effects of soy Morotomi, M., Nagai, F., Watanabe, Y., and Tanaka, R. (2010). Succinatimonas protein and isoflavones on glycemic control and insulin sensitivity: a 6-mo hippei gen. nov., sp. nov., isolated from human faeces. Int. J. Syst. Evol. double-blind, randomized, placebo-controlled trial in postmenopausal Chinese Microbiol. 60(Pt 8), 1788–1793. doi: 10.1099/ijs.0.015958-0 women with prediabetes or untreated early diabetes. Am. J. Clin. Nutr. 91, Morrison, D. J., and Preston, T. (2016). Formation of short chain fatty acids by 1394–1401. doi: 10.3945/ajcn.2009.28813 the gut microbiota and their impact on human metabolism. Gut Microbes 7, Lloyd-Price, J., Abu-Ali, G., and Huttenhower, C. (2016). The healthy human 189–200. doi: 10.1080/19490976.2015.1134082 microbiome. Genome Med. 8, 51. doi: 10.1186/s13073-016-0307-y Mourembou, G., Rathored, J., Lekana-Douki, J. B., Ndjoyi-Mbiguino, A., Loubinoux, J., Bronowicki, J. P., Pereira, I. A., Mougenel, J. L., and Faou, A. Khelaifia, S., Robert, C., et al. (2016). Description of Gabonibacter massiliensis E. (2002). Sulfate-reducing bacteria in human feces and their association gen. nov., sp. nov., a new member of the family porphyromonadaceae with inflammatory bowel diseases. FEMS Microbiol. Ecol. 40, 107–112. isolated from the human gut microbiota. Curr. Microbiol. 73, 867–877. doi: 10.1111/j.1574-6941.2002.tb00942.x doi: 10.1007/s00284-016-1137-2 Louis, P., Young, P., Holtrop, G., and Flint, H. J. (2010). Diversity of Nadkarni, P., Chepurny, O. G., and Holz, G. G. (2014). Regulation of human colonic butyrate-producing bacteria revealed by analysis of the glucose homeostasis by GLP-1. Prog. Mol. Biol. Transl. Sci. 121, 23–65. butyryl-CoA:acetate CoA-transferase gene. Environ. Microbiol. 12, 304–314. doi: 10.1016/B978-0-12-800101-1.00002-8 doi: 10.1111/j.1462-2920.2009.02066.x Nagai, F., Morotomi, M., Sakon, H., and Tanaka, R. (2009). Parasutterella Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K., and Knight, R. excrementihominis gen. nov., sp. nov., a member of the family Alcaligenaceae (2012). Diversity, stability and resilience of the human gut microbiota. Nature isolated from human faeces. Int. J. Syst. Evol. Microbiol. 59(Pt 7), 1793–1797. 489, 220–230. doi: 10.1038/nature.11550 doi: 10.1099/ijs.0.002519-0 Malaguarnera, M., Vacante, M., Antic, T., Giordano, M., Chisari, G., Acquaviva, Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., and Creutzfeldt, R., et al. (2012). Bifidobacterium longum with fructo-oligosaccharides in W. (1993). Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] patients with non alcoholic steatohepatitis. Dig. Dis. Sci. 57, 545–553. but not of synthetic human gastric inhibitory polypeptide in patients with doi: 10.1007/s10620-011-1887-4 type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307. doi: 10.1172/JCI116186 Mao, B., Li, D., Zhao, J., Liu, X., Gu, Z., Chen, Y. Q., et al. (2015). Ndongo, S., Dubourg, G., Khelaifia, S., Fournier, P. E., and Raoult, D. (2016a). Metagenomic insights into the effects of fructo-oligosaccharides (FOS) on the Christensenella timonensis, a new bacterial species isolated from the human composition of fecal microbiota in mice. J. Agric. Food Chem. 63, 856–863. gut. New Microbes New Infect 13, 32–33. doi: 10.1016/j.nmni.2016.05.010 doi: 10.1021/jf505156h Ndongo, S., Khelaifia, S., Fournier, P. E., and Raoult, D. (2016b). Christensenella Marin, L., Miguelez, E. M., Villar, C. J., and Lombo, F. (2015). Bioavailability of massiliensis, a new bacterial species isolated from the human gut. New Microbes dietary polyphenols and gut microbiota metabolism: antimicrobial properties. New Infect. 12, 69–70. doi: 10.1016/j.nmni.2016.04.014 Biomed Res. Int. 2015:905215. doi: 10.1155/2015/905215 Nettleton, J. A., Harnack, L. J., Scrafford, C. G., Mink, P. J., Barraj, L. M., and Jacobs, Marquez-Aguirre, A. L., Camacho-Ruiz, R. M., Gutierrez-Mercado, Y. K., Padilla- D. R. Jr. (2006). Dietary flavonoids and flavonoid-rich foods are not associated Camberos, E., Gonzalez-Avila, M., Galvez-Gastelum, F. J., et al. (2016). with risk of type 2 diabetes in postmenopausal women. J. Nutr. 136, 3039–3045. Fructans from agave tequilana with a lower degree of polymerization prevent Newton, D. F., Cummings, J. H., Macfarlane, S., and Macfarlane, G. weight gain, hyperglycemia and liver steatosis in high-fat diet-induced obese T. (1998). Growth of a human intestinal Desulfovibrio desulfuricans mice. Plant Foods Hum. Nutr. 71, 416–421. doi: 10.1007/s11130-016-0578-x in continuous cultures containing defined populations of saccharolytic Marshall, B. J., and Warren, J. R. (1984). Unidentified curved bacilli in the and amino acid fermenting bacteria. J. Appl. Microbiol. 85, 372–380. stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311–1315. doi: 10.1046/j.1365-2672.1998.00522.x doi: 10.1016/S0140-6736(84)91816-6 Neyrinck, A. M., Van Hee, V. F., Piront, N., De Backer, F., Toussaint, O., Cani, P. Martinez, K. B., Pierre, J. F., and Chang, E. B. (2016). The gut microbiota: the D., et al. (2012). Wheat-derived arabinoxylan oligosaccharides with prebiotic gateway to improved metabolism. Gastroenterol. Clin. North Am. 45, 601–614. effect increase satietogenic gut peptides and reduce metabolic endotoxemia in doi: 10.1016/j.gtc.2016.07.001 diet-induced obese mice. Nutr. Diabetes 2:e28. doi: 10.1038/nutd.2011.24 Masumoto, S., Terao, A., Yamamoto, Y., Mukai, T., Miura, T., and Shoji, T. O’Hara, A. M., and Shanahan, F. (2006). The gut flora as a forgotten organ. EMBO (2016). Non-absorbable apple procyanidins prevent obesity associated with Rep. 7, 688–693. doi: 10.1038/sj.embor.7400731 gut microbial and metabolomic changes. Sci. Rep. 6:31208. doi: 10.1038/srep Olli, K., Salli, K., Alhoniemi, E., Saarinen, M., Ibarra, A., Vasankari, T., et al. 31208 (2015). Postprandial effects of polydextrose on satiety hormone responses

Frontiers in Pharmacology | www.frontiersin.org 26 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

and subjective feelings of appetite in obese participants. Nutr. J. 14:2. Ramasamy, D., Lagier, J. C., Nguyen, T. T., Raoult, D., and Fournier, P. E. doi: 10.1186/1475-2891-14-2 (2013). Non contiguous-finished genome sequence and description of Dielma Ott, S. J., Kuhbacher, T., Musfeldt, M., Rosenstiel, P., Hellmig, S., Rehman, fastidiosa gen. nov., sp. nov., a new member of the Family Erysipelotrichaceae. A., et al. (2008). Fungi and inflammatory bowel diseases: alterations Stand. Genomic Sci. 8, 336–351. doi: 10.4056/sigs.3567059 of composition and diversity. Scand. J. Gastroenterol. 43, 831–841. Ramirez-Farias, C., Slezak, K., Fuller, Z., Duncan, A., Holtrop, G., and Louis, doi: 10.1080/00365520801935434 P. (2009). Effect of inulin on the human gut microbiota: stimulation of Ozdal, T., Sela, D. A., Xiao, J., Boyacioglu, D., Chen, F., and Capanoglu, E. (2016). Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br. J. Nutr. 101, The reciprocal interactions between polyphenols and gut microbiota and effects 541–550. doi: 10.1017/S0007114508019880 on bioaccessibility. Nutrients 8:78. doi: 10.3390/nu8020078 Rehman, A., Rausch, P., Wang, J., Skieceviciene, J., Kiudelis, G., Bhagalia, Pace, N. R. (2006). Time for a change. Nature 441:289. doi: 10.1038/441289a K., et al. (2016). Geographical patterns of the standing and active Paeschke, T. M., and Aimutis, W. R. (eds.). (2010). “Appendix nondigestible human gut microbiome in health and IBD. Gut 65, 238–248. carbohydrates: structure and sources,” in Nondigestible Carbohydrates and doi: 10.1136/gutjnl-2014-308341 Digestive Health (Ames, IA: Blackwell Publishing Ltd.), 321–329. Reiser, S. (1985). Effect of dietary sugars on metabolic risk factors associated with Pandey, K. B., and Rizvi, S. I. (2009). Plant polyphenols as dietary antioxidants heart disease. Nutr. Health 3, 203–216. in human health and disease. Oxid. Med. Cell. Longev. 2, 270–278. Rendon-Huerta, J. A., Juarez-Flores, B., Pinos-Rodriguez, J. M., Aguirre-Rivera, doi: 10.4161/oxim.2.5.9498 J. R., and Delgado-Portales, R. E. (2012). Effects of different sources of Parekh, P. J., Arusi, E., Vinik, A. I., and Johnson, D. A. (2014). The role and fructans on body weight, blood metabolites and fecal bacteria in normal influence of gut microbiota in pathogenesis and management of obesity and and obese non-diabetic and diabetic rats. Plant Foods Hum. Nutr. 67, 64–70. metabolic syndrome. Front. Endocrinol. 5:47. doi: 10.3389/fendo.2014.00047 doi: 10.1007/s11130-011-0266-9 Parfrey, L. W., Walters, W. A., and Knight, R. (2011). Microbial eukaryotes in the Rial, S. A., Karelis, A. D., Bergeron, K.-F., and Mounier, C. (2016). Gut microbiota human microbiome: ecology, evolution, and future directions. Front. Microbiol. and metabolic health: the potential beneficial effects of a medium chain 2:153. doi: 10.3389/fmicb.2011.00153 triglyceride diet in obese individuals. Nutrients 8:281. doi: 10.3390/nu8050281 Parkar, S. G., Stevenson, D. E., and Skinner, M. A. (2008). The potential influence Richards, A. L., Burns, M. B., Alazizi, A., Barreiro, L. B., Pique-Regi, of fruit polyphenols on colonic microflora and human gut health. Int. J. Food R., Blekhman, R., et al. (2016). Genetic and transcriptional analysis of Microbiol. 124, 295–298. doi: 10.1016/j.ijfoodmicro.2008.03.017 human host response to healthy gut microbiota. mSystems 1:e00067-16. Parnell, J. A., and Reimer, R. A. (2009). Weight loss during oligofructose doi: 10.1128/mSystems.00067-16 supplementation is associated with decreased ghrelin and increased peptide Riviere, A., Selak, M., Lantin, D., Leroy, F., and De Vuyst, L. (2016). YY in overweight and obese adults. Am. J. Clin. Nutr. 89, 1751–1759. Bifidobacteria and butyrate-producing colon bacteria: importance and doi: 10.3945/ajcn.2009.27465 strategies for their stimulation in the human gut. Front. Microbiol. 7:979. Peirce, V., and Vidal-Puig, A. (2013). Regulation of glucose homoeostasis doi: 10.3389/fmicb.2016.00979 by brown adipose tissue. Lancet Diabetes Endocrinol. 1, 353–360. Roberfroid, M., Gibson, G. R., Hoyles, L., McCartney, A. L., Rastall, R., Rowland, doi: 10.1016/S2213-8587(13)70055-X I., et al. (2010). Prebiotic effects: metabolic and health benefits. Br. J. Nutr. Pereira, D. M., Valentão, P., Pereira, J. A., and Andrade, P. B. (2009). 104(Suppl. 2), S1–S63. doi: 10.1017/s0007114510003363 Phenolics: from chemistry to biology. Molecules 14, 2202–2211. Roopchand, D. E., Carmody, R. N., Kuhn, P., Moskal, K., Rojas-Silva, P., doi: 10.3390/molecules14062202 Turnbaugh, P. J., et al. (2015). Dietary polyphenols promote growth of Piche, T., des Varannes, S. B., Sacher-Huvelin, S., Holst, J. J., Cuber, J. C., and the gut bacterium Akkermansia muciniphila and attenuate high-fat diet- Galmiche, J. P. (2003). Colonic fermentation influences lower esophageal induced metabolic syndrome. Diabetes 64, 2847–2858. doi: 10.2337/db sphincter function in gastroesophageal reflux disease. Gastroenterology 124, 14-1916 894–902. doi: 10.1053/gast.2003.50159 Rosenbaum, M., Knight, R., and Leibel, R. L. (2015). The gut microbiota in human Pyra, K. A., Saha, D. C., and Reimer, R. A. (2012). Prebiotic fiber increases energy homeostasis and obesity. Trends Endocrinol. Metab. 26, 493–501. hepatic acetyl CoA carboxylase phosphorylation and suppresses glucose- doi: 10.1016/j.tem.2015.07.002 dependent insulinotropic polypeptide secretion more effectively when used Russell, W. R., Labat, A., Scobbie, L., Duncan, G. J., and Duthie, G. G. with metformin in obese rats. J. Nutr. 142, 213–220. doi: 10.3945/jn.111. (2009). Phenolic acid content of fruits commonly consumed and locally 147132 produced in Scotland. Food Chem. 115, 100–104. doi: 10.1016/j.foodchem.2008. Qiao, Y., Sun, J., Xia, S., Tang, X., Shi, Y., and Le, G. (2014). Effects of resveratrol on 11.086 gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Russo, F., Chimienti, G., Riezzo, G., Pepe, G., Petrosillo, G., Chiloiro, M., et al. Food Funct. 5, 1241–1249. doi: 10.1039/c3fo60630a (2008). Inulin-enriched pasta affects lipid profile and Lp(a) concentrations Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., et al. in Italian young healthy male volunteers. Eur. J. Nutr. 47, 453–459. (2010). A human gut microbial gene catalogue established by metagenomic doi: 10.1007/s00394-008-0748-1 sequencing. Nature 464, 59–65. doi: 10.1038/nature08821 Sakamoto, M., and Benno, Y. (2006). Reclassification of Bacteroides distasonis, Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., et al. (2012). A metagenome- Bacteroides goldsteinii and Bacteroides merdae as Parabacteroides distasonis gen. wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60. nov., comb. nov., Parabacteroides goldsteinii comb. nov. and Parabacteroides doi: 10.1038/nature11450 merdae comb. nov. Int. J. Syst. Evol. Microbiol. 56(Pt 7), 1599–1605. Quigley, E. M. (2013). Gut bacteria in health and disease. Gastroenterol. Hepatol. doi: 10.1099/ijs.0.64192-0 9, 560–569. Sakamoto, M., and Ohkuma, M. (2012). Reclassification of Xylanibacter oryzae Rajilic-Stojanovic, M., and de Vos, W. M. (2014). The first 1000 cultured species Ueki et al. 2006 as Prevotella oryzae comb. nov., with an emended description of the human gastrointestinal microbiota. FEMS Microbiol. Rev. 38, 996–1047. of the genus Prevotella. Int. J. Syst. Evol. Microbiol. 62(Pt 11), 2637–2642. doi: 10.1111/1574-6976.12075 doi: 10.1099/ijs.0.038638-0 Rajilic-Stojanovic, M., Shanahan, F., Guarner, F., and de Vos, W. M. (2013). Salazar, N., Dewulf, E. M., Neyrinck, A. M., Bindels, L. B., Cani, P. D., Mahillon, J., Phylogenetic analysis of dysbiosis in ulcerative colitis during remission. et al. (2015). Inulin-type fructans modulate intestinal Bifidobacterium species Inflamm. Bowel Dis. 19, 481–488. doi: 10.1097/MIB.0b013e31827fec6d populations and decrease fecal short-chain fatty acids in obese women. Clin. Rajilic-Stojanovic, M., Smidt, H., and de Vos, W. M. (2007). Diversity of the human Nutr. 34, 501–507. doi: 10.1016/j.clnu.2014.06.001 gastrointestinal tract microbiota revisited. Environ. Microbiol. 9, 2125–2136. Samuel, B. S., Hansen, E. E., Manchester, J. K., Coutinho, P. M., Henrissat, doi: 10.1111/j.1462-2920.2007.01369.x B., Fulton, R., et al. (2007). Genomic and metabolic adaptations of Rajpal, D. K., Klein, J. L., Mayhew, D., Boucheron, J., Spivak, A. T., Kumar, Methanobrevibacter smithii to the human gut. Proc. Natl. Acad. Sci. U.S.A. 104, V., et al. (2015). Selective spectrum antibiotic modulation of the gut 10643–10648. doi: 10.1073/pnas.0704189104 microbiome in obesity and diabetes rodent models. PLoS ONE 10:e0145499. Santacruz, A., Collado, M. C., Garcia-Valdes, L., Segura, M. T., Martin-Lagos, J. A., doi: 10.1371/journal.pone.0145499 Anjos, T., et al. (2010). Gut microbiota composition is associated with body

Frontiers in Pharmacology | www.frontiersin.org 27 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

weight, weight gain and biochemical parameters in pregnant women. Br. J. Tilg, H., and Moschen, A. R. (2014). Microbiota and diabetes: an evolving Nutr. 104, 83–92. doi: 10.1017/S0007114510000176 relationship. Gut 63, 1513–1521. doi: 10.1136/gutjnl-2014-306928 Scalbert, A., Manach, C., Morand, C., Remesy, C., and Jimenez, L. (2005). Dietary Tsao, R. (2010). Chemistry and biochemistry of dietary polyphenols. Nutrients 2, polyphenols and the prevention of diseases. Crit. Rev. Food Sci. Nutr. 45, 1231–1246. doi: 10.3390/nu2121231 287–306. doi: 10.1080/1040869059096 Turnbaugh, P. J., Hamady, M., Yatsunenko, T., Cantarel, B. L., Duncan, A., Ley, R. Scarpellini, E., Ianiro, G., Attili, F., Bassanelli, C., De Santis, A., and Gasbarrini, E., et al. (2009). A core gut microbiome in obese and lean twins. Nature 457, A. (2015). The human gut microbiota and virome: potential therapeutic 480–484. doi: 10.1038/nature07540 implications. Digest. Liver Dis. 47, 1007–1012. doi: 10.1016/j.dld.2015.07.008 Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., and Schaefer, E. J., Gleason, J. A., and Dansinger, M. L. (2009). Dietary fructose Gordon, J. I. (2006). An obesity-associated gut microbiome with increased and glucose differentially affect lipid and glucose homeostasis. J. Nutr. 139, capacity for energy harvest. Nature 444, 1027–1031. doi: 10.1038/nature05414 1257S–1262S. doi: 10.3945/jn.108.098186 Umeno, A., Horie, M., Murotomi, K., Nakajima, Y., and Yoshida, Y. (2016). Schneeberger, M., Everard, A., Gómez-Valadés, A. G., Matamoros, S., Ramírez, Antioxidative and antidiabetic effects of natural polyphenols and isoflavones. S., Delzenne, N. M., et al. (2015). Akkermansia muciniphila inversely Molecules 21:708. doi: 10.3390/molecules21060708 correlates with the onset of inflammation, altered adipose tissue metabolism Unemo, M., Golparian, D., and Hellmark, B. (2014). First three Neisseria and metabolic disorders during obesity in mice. Sci. Rep. 5:16643. gonorrhoeae isolates with high-level resistance to azithromycin in doi: 10.1038/srep16643 Sweden: a threat to currently available dual-antimicrobial regimens for Selma, M. V., Espin, J. C., and Tomas-Barberan, F. A. (2009). Interaction between treatment of gonorrhea? Antimicrob. Agents Chemother. 58, 624–625. phenolics and gut microbiota: role in human health. J. Agric. Food Chem. 57, doi: 10.1128/AAC.02093-13 6485–6501. doi: 10.1021/jf902107d Ursell, L. K., Clemente, J. C., Rideout, J. R., Gevers, D., Caporaso, J. G., and Knight, Shi, Y. C., Loh, K., Bensellam, M., Lee, K., Zhai, L., Lau, J., et al. (2015). Pancreatic R. (2012). The interpersonal and intrapersonal diversity of human-associated PYY is critical in the control of insulin secretion and glucose homeostasis in microbiota in key body sites. J. Allergy Clin. Immunol. 129, 1204–1208. female mice. Endocrinology 156, 3122–3136. doi: 10.1210/en.2015-1168 doi: 10.1016/j.jaci.2012.03.010 Shin, N. R., Whon, T. W., and Bae, J. W. (2015). Proteobacteria: microbial Vaahtovuo, J., Korkeamaki, M., Munukka, E., Viljanen, M. K., and Toivanen, signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503. P. (2005). Quantification of bacteria in human feces using 16S rRNA- doi: 10.1016/j.tibtech.2015.06.011 hybridization, DNA-staining and flow cytometry. J. Microbiol. Methods 63, Shrime, M. G., Bauer, S. R., McDonald, A. C., Chowdhury, N. H., Coltart, C. 276–286. doi: 10.1016/j.mimet.2005.03.017 E., and Ding, E. L. (2011). Flavonoid-rich cocoa consumption affects multiple Valsecchi, C., Carlotta Tagliacarne, S., and Castellazzi, A. (2016). Gut cardiovascular risk factors in a meta-analysis of short-term studies. J. Nutr. 141, microbiota and obesity. J. Clin. Gastroenterol. 50(Suppl. 2), S157–S158. 1982–1988. doi: 10.3945/jn.111.145482 doi: 10.1097/mcg.0000000000000715 Smith, M. I., Yatsunenko, T., Manary, M. J., Trehan, I., Mkakosya, R., Cheng, Van den Abbeele, P., Gerard, P., Rabot, S., Bruneau, A., El Aidy, S., Derrien, M., J., et al. (2013). Gut microbiomes of Malawian twin pairs discordant for et al. (2011). Arabinoxylans and inulin differentially modulate the mucosal and kwashiorkor. Science 339, 548–554. doi: 10.1126/science.1229000 luminal gut microbiota and mucin-degradation in humanized rats. Environ. Sokol, H., Leducq, V., Aschard, H., Pham, H. P., Jegou, S., Landman, C., Microbiol. 13, 2667–2680. doi: 10.1111/j.1462-2920.2011.02533.x et al. (2016). Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048. Van Houte, J., and Gibbons, R. J. (1966). Studies of the cultivable flora of normal doi: 10.1136/gutjnl-2015-310746 human feces. Antonie Van Leeuwenhoek 32, 212–222. doi: 10.1007/BF02097463 Song, Y., Kononen, E., Rautio, M., Liu, C., Bryk, A., Eerola, E., et al. (2006). Alistipes Vinayagam, R., and Xu, B. (2015). Antidiabetic properties of dietary onderdonkii sp. nov. and Alistipes shahii sp. nov., of human origin. Int. J. Syst. flavonoids: a cellular mechanism review. Nutr. Metab. 12:60. Evol. Microbiol. 56(Pt 8), 1985–1990. doi: 10.1099/ijs.0.64318-0 doi: 10.1186/s12986-015-0057-7 Song, Y., Manson, J. E., Buring, J. E., Sesso, H. D., and Liu, S. (2005). Associations of Vrieze, A., Van Nood, E., Holleman, F., Salojärvi, J., Kootte, R. S., Bartelsman, dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance J. F. W. M., et al. (2012). Transfer of intestinal microbiota from lean and systemic inflammation in women: a prospective study and cross-sectional donors increases insulin sensitivity in individuals with metabolic syndrome. analysis. J. Am. Coll. Nutr. 24, 376–384. doi: 10.1080/07315724.2005.10719488 Gastroenterology 143, 913.e917–916.e917. doi: 10.1053/j.gastro.2012.06.031 Stanford, K. I., Middelbeek, R. J., Townsend, K. L., An, D., Nygaard, Walter, J., Margosch, D., Hammes, P. W., and Hertel, C. (2002). Detection of E. B., Hitchcox, K. M., et al. (2013). Brown adipose tissue regulates fusobacterium species in human feces using genus-specific PCR primers and glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223. denaturing gradient gel electrophoresis. Microb. Ecol. Health Dis. 14, 129–132. doi: 10.1172/JCI62308 doi: 10.1080/089106002320644294 Stephen, A. M., and Cummings, J. H. (1980). The microbial contribution to human Walters, W. A., Xu, Z., and Knight, R. (2014). Meta-analyses of human gut faecal mass. J. Med. Microbiol. 13, 45–56. doi: 10.1099/00222615-13-1-45 microbes associated with obesity and IBD. FEBS Lett. 588, 4223–4233. Stevens, J. F., and Maier, C. S. (2016). The chemistry of gut microbial metabolism doi: 10.1016/j.febslet.2014.09.039 of polyphenols. Phytochem. Rev. 15, 425–444. doi: 10.1007/s11101-016-9459-z Walther, W. W., and Millwood, E. G. (1951). Presence of certain serological Swidsinski, A., Dorffel, Y., Loening-Baucke, V., Tertychnyy, A., Biche-Ool, S., types of Bact. coli in the human intestine. Br. Med. J. 2, 156–157. Stonogin, S., et al. (2012). Mucosal invasion by fusobacteria is a common doi: 10.1136/bmj.2.4724.156 feature of acute appendicitis in Germany, Russia, and China. Saudi J. Wang, D., Ho, L., Faith, J., Ono, K., Janle, E. M., Lachcik, P. J., et al. (2015). Role Gastroenterol. 18, 55–58. doi: 10.4103/1319-3767.91734 of intestinal microbiota in the generation of polyphenol derived phenolic acid Tang, W. H., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., et al. (2013). mediated attenuation of Alzheimer’s disease β-amyloid oligomerization. Mol. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular Nutr. Food Res. 59, 1025–1040. doi: 10.1002/mnfr.201400544 risk. N. Engl. J. Med. 368, 1575–1584. doi: 10.1056/NEJMoa1109400 Wang, H. X., and Wang, Y. P. (2016). Gut microbiota-brain axis. Chin. Med. J. 129, Taras, D., Simmering, R., Collins, M. D., Lawson, P. A., and Blaut, M. (2002). 2373–2380. doi: 10.4103/0366-6999.190667 Reclassification of Eubacterium formicigenerans Holdeman and Moore 1974 Wang, M., Ahrne, S., Jeppsson, B., and Molin, G. (2005). Comparison of as Dorea formicigenerans gen. nov., comb. nov., and description of Dorea bacterial diversity along the human intestinal tract by direct cloning longicatena sp. nov., isolated from human faeces. Int. J. Syst. Evol. Microbiol. and sequencing of 16S rRNA genes. FEMS Microbiol. Ecol. 54, 219–231. 52(Pt 2), 423–428. doi: 10.1099/00207713-52-2-423 doi: 10.1016/j.femsec.2005.03.012 Thilakarathna, S. H., and Rupasinghe, H. P. (2013). Flavonoid bioavailability Wang, S., Moustaid-Moussa, N., Chen, L., Mo, H., Shastri, A., Su, R., et al. (2014). and attempts for bioavailability enhancement. Nutrients 5, 3367–3387. Novel insights of dietary polyphenols and obesity. J. Nutr. Biochem. 25, 1–18. doi: 10.3390/nu5093367 doi: 10.1016/j.jnutbio.2013.09.001 Thilesen, C. M., Nicolaidis, M., Lokebo, J. E., Falsen, E., Jorde, A. T., and Muller, F. Wang, X., Liu, H., Chen, J., Li, Y., and Qu, S. (2015). Multiple factors related (2007). Leptotrichia amnionii, an emerging pathogen of the female urogenital to the secretion of glucagon-like peptide-1. Int. J. Endocrinol. 2015:651757. tract. J. Clin. Microbiol. 45, 2344–2347. doi: 10.1128/JCM.00167-07 doi: 10.1155/2015/651757

Frontiers in Pharmacology | www.frontiersin.org 28 June 2017 | Volume 8 | Article 387 Eid et al. Microbiota, Medicinal Plants, and Food Ingredients

Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., Dugar, B., et al. (2011). Yamaguchi, Y., Adachi, K., Sugiyama, T., Shimozato, A., Ebi, M., Ogasawara, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. N., et al. (2016). Association of intestinal microbiota with metabolic markers Nature 472, 57–63. doi: 10.1038/nature09922 and dietary habits in patients with type 2 diabetes. Digestion 94, 66–72. Wexler, H. M. (2007). Bacteroides: the good, the bad, and the nitty-gritty. Clin. doi: 10.1159/000447690 Microbiol. Rev. 20, 593–621. doi: 10.1128/CMR.00008-07 Yatsunenko, T., Rey, F. E., Manary, M. J., Trehan, I., Dominguez-Bello, M. G., Wexler, H. M., Reeves, D., Summanen, P. H., Molitoris, E., McTeague, M., Contreras, M., et al. (2012). Human gut microbiome viewed across age and Duncan, J., et al. (1996). Sutterella wadsworthensis gen. nov., sp. nov., bile- geography. Nature 486, 222–227. doi: 10.1038/nature11053 resistant microaerophilic Campylobacter gracilis-like clinical isolates. Int. J. Ze, X., Duncan, S. H., Louis, P., and Flint, H. J. (2012). Ruminococcus bromii is Syst. Bacteriol. 46, 252–258. doi: 10.1099/00207713-46-1-252 a keystone species for the degradation of resistant starch in the human colon. Williams, C. M. (1999). Effects of inulin on lipid parameters in humans. J. Nutr. ISME J. 6, 1535–1543. doi: 10.1038/ismej.2012.4 129(7 Suppl.), 1471S–1473S. Zhang, W., Gu, Y., Chen, Y., Deng, H., Chen, L., Chen, S., et al. (2010). Intestinal Williamson, G. (2013). Possible effects of dietary polyphenols on sugar absorption flora imbalance results in altered bacterial translocation and liver function in and digestion. Mol. Nutr. Food Res. 57, 48–57. doi: 10.1002/mnfr.201200511 rats with experimental cirrhosis. Eur. J. Gastroenterol. Hepatol. 22, 1481–1486. Woese, C. R., Kandler, O., and Wheelis, M. L. (1990). Towards a natural system doi: 10.1097/meg.0b013e32833eb8b0 of organisms: proposal for the domains Archaea, Bacteria, and Eucarya. Proc. Zhang, Y., and Zhang, H. (2013). Microbiota associated with type 2 diabetes Natl. Acad. Sci. U.S.A. 87, 4576–4579. doi: 10.1073/pnas.87.12.4576 and its related complications. Food Sci. Hum. Wellness 2, 167–172. Woods, M., and Gorbach, S. (2001). “Influences of fiber on the ecology of the doi: 10.1016/j.fshw.2013.09.002 intestinal flora,” in CRC Handbook of Dietary Fiber in Human Nutrition, 3rd Zilberstein, B., Quintanilha, A. G., Santos, M. A., Pajecki, D., Moura, E. G., Alves, Edn., ed G. A. Spiller (CRC Press), 257–270. P. R., et al. (2007). Digestive tract microbiota in healthy volunteers. Clinics (Sao Wroblewski, L. E., and Peek, R. M. Jr. (2016). Helicobacter pylori, Paulo) 62, 47–54. doi: 10.1590/S1807-59322007000100008 cancer, and the gastric microbiota. Adv. Exp. Med. Biol. 908, 393–408. Zoetendal, E. G., Raes, J., van den Bogert, B., Arumugam, M., Booijink, C. C., doi: 10.1007/978-3-319-41388-4_19 Troost, F. J., et al. (2012). The human small intestinal microbiota is driven by Wu, G. D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y. Y., Keilbaugh, S. A., rapid uptake and conversion of simple carbohydrates. ISME J. 6, 1415–1426. et al. (2011). Linking long-term dietary patterns with gut microbial enterotypes. doi: 10.1038/ismej.2011.212 Science 334, 105–108. doi: 10.1126/science.1208344 Zou, S., Caler, L., Colombini-Hatch, S., Glynn, S., and Srinivas, P. (2016). Research Wu, T., Yang, Y., Zhang, L., and Han, J. (2010). [Systematic review of the effects of on the human virome: where are we and what is next. Microbiome 4:32. inulin-type fructans on blood lipid profiles: a meta-analysis]. Wei Sheng Yan Jiu doi: 10.1186/s40168-016-0177-y 39, 172–176. Zubrzycki, L., and Spaulding, E. H. (1962). Studies on the stability of the normal Wylie, K. M., Mihindukulasuriya, K. A., Zhou, Y., Sodergren, E., Storch, G. human fecal flora. J. Bacteriol. 83, 968–974. A., and Weinstock, G. M. (2014). Metagenomic analysis of double-stranded DNA viruses in healthy adults. BMC Biol. 12:71. doi: 10.1186/s12915-014- Conflict of Interest Statement: The authors declare that the research was 0071-7 conducted in the absence of any commercial or financial relationships that could Xu, J., Bjursell, M. K., Himrod, J., Deng, S., Carmichael, L. K., Chiang, H. C., et al. be construed as a potential conflict of interest. (2003). A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076. doi: 10.1126/science.1080029 Copyright © 2017 Eid, Wright, Anil Kumar, Qawasmeh, Hassan, Mocan, Nabavi, Xu, J., Mahowald, M. A., Ley, R. E., Lozupone, C. A., Hamady, M., Martens, E. C., Rastrelli, Atanasov and Haddad. This is an open-access article distributed under the et al. (2007). Evolution of symbiotic bacteria in the distal human intestine. PLoS terms of the Creative Commons Attribution License (CC BY). The use, distribution or Biol. 5:e156. doi: 10.1371/journal.pbio.0050156 reproduction in other forums is permitted, provided the original author(s) or licensor Yabe, D., and Seino, Y. (2011). Two incretin hormones GLP-1 and GIP: comparison are credited and that the original publication in this journal is cited, in accordance of their actions in insulin secretion and beta cell preservation. Prog. Biophys. with accepted academic practice. No use, distribution or reproduction is permitted Mol. Biol. 107, 248–256. doi: 10.1016/j.pbiomolbio.2011.07.010 which does not comply with these terms.

Frontiers in Pharmacology | www.frontiersin.org 29 June 2017 | Volume 8 | Article 387